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D N Granger

Publications and source records attributed to D N Granger.

At least 55 records · Page 3Linked to original sources
PubMed2000

Regulation of E-selectin expression in postischemic intestinal microvasculature.

Monolayers of cultured endothelial cells exposed to hypoxia-reoxygenation exhibit a transcription-dependent increase in E-selectin expression and E-selectin-dependent neutrophil-endothelial cell adhesion. The overall objectives of this study were 1) to determine whether ischemia-reperfusion (I/R) promotes upregulation of E-selectin in vivo; 2) if so, to define the mediators of this response; and 3) to assess the contribution of E-selectin to I/R-induced neutrophil recruitment. The dual-radiolabeled monoclonal antibody (MAb) technique was used to measure E-selectin expression in the intestinal vasculature. Ischemia was induced by complete occlusion (30-60 min) of the superior mesenteric artery followed by 3-24 h of reperfusion. Increasing durations of ischemia elicited progressively increasing (2- to 5-fold) levels of E-selectin expression, with the peak response noted after 45 min of ischemia and 5 h of reperfusion. Subsequent experiments revealed that I/R-induced increase in E-selectin expression (at 5 h) is significantly blunted in transgenic mice that overexpress Cu,Zn-superoxide dismutase or by treatment of wild-type mice with either a blocking antibody against tumor necrosis factor (TNF)-alpha or an inhibitor of nuclear factor-kappaB (NF-kappaB) activation (PS341). Administration of an E-selectin-specific MAb dramatically reduced I/R-induced recruitment of neutrophils in the intestine. These findings suggest that superoxide and TNF-alpha mediate gut I/R-induced E-selectin expression via an NF-kappaB-dependent mechanism; this upregulation of E-selectin contributes significantly to I/R-induced neutrophil recruitment.

Animals↗
PubMed2000

Enteric microflora contribute to constitutive ICAM-1 expression on vascular endothelial cells.

Quantitative estimates of endothelial cell adhesion molecule expression have revealed that some adhesion molecules [e.g., intercellular adhesion molecule-1 (ICAM-1)] are abundantly expressed in different vascular beds under normal conditions. The objective of this study was to determine whether the enteric microflora contribute to the constitutive expression of ICAM-1 and other endothelial cell adhesion molecules in the gastrointestinal tract and other regional vascular beds. The dual radiolabeled monoclonal antibody technique was used to measure endothelial expression of ICAM-1, ICAM-2, vascular cell adhesion molecule-1 (VCAM-1), and E-selectin in conventional, germ-free mice and germ-free mice receiving the cecal contents of conventional mice to reestablish the enteric microflora (total association). Constitutive ICAM-1 expression was significantly lower in the splanchnic organs (pancreas, stomach, small and large intestine, mesentery, and liver), kidneys, skeletal muscle, and skin of germ-free mice compared with their conventional counterparts. These differences were abolished after total association of germ-free mice with the indigenous gastrointestinal flora. The expression of ICAM-2, VCAM-1, and E-selectin in the various tissues studied did not differ between conventional and germ-free mice. These findings indicate that the indigenous gastrointestinal microflora are responsible for a significant proportion of the basal ICAM-1 expression detected in both intestinal and extraintestinal tissues.

Animals↗
PubMed2000

Endothelin-1-induced PMN infiltration and mucosal dysfunction in the rat small intestine.

The objectives of this study were to characterize the effects of endothelin (ET)-1 on intestinal mucosal parameters and to assess the contribution of polymorphonuclear leukocytes (PMNs), intercellular adhesion molecule-1 (ICAM-1), and a platelet-activating factor (PAF) to the mucosal dysfunction induced by ET-1. Different concentrations of ET-1 (100, 200, and 400 pmol/kg) were infused into the superior mesenteric artery for 10 min, and tissue samples were obtained 30 min after terminating the infusion. ET-1 administration significantly elevated tissue myeloperoxidase activity, plasma carbonyl content, and tissue chemiluminescence intensity, indicating that ET-1 produces PMN infiltration and oxidant stress. Blood-to-lumen clearance of (51)Cr-EDTA significantly increased after ET-1 infusion (400 pmol/kg). Monoclonal antibodies against ICAM-1 (1A29, 2 mg/kg), antineutrophil serum, and PAF antagonist (WEB-2086, 10 mg/kg) attenuated the mucosal barrier dysfunction induced by ET-1. Overall, our data indicate that ET-1 causes PMN accumulation, oxidant stress, and mucosal dysfunction in the rat small intestine and that ET-1-induced mucosal dysfunction involves a mechanism that includes a role for PMNs, ICAM-1, and PAF.

Animals↗
PubMed2000

Hepatic microvascular responses to ischemia-reperfusion in low-density lipoprotein receptor knockout mice.

The overall objective of this study was to determine whether genetically induced hypercholesterolemia alters the inflammatory and microvascular responses of mouse liver to ischemia-reperfusion (I/R). The accumulation of rhodamine 6G-labeled leukocytes and the number of nonperfused sinusoids (NPS) were monitored (by intravital microscopy) in the liver of wild-type (WT) and low-density lipoprotein receptor-deficient (LDLr(-/-)) mice for 1 h after a 30-min period of normothermic ischemia. Plasma alanine transaminase (ALT) levels were used to monitor hepatocellular injury. Microvascular leukostasis as well as increases in NPS and plasma ALT were observed at 60 min after hepatic I/R in both WT and in LDLr(-/-) mice; however, these responses were greatly exaggerated in LDLr(-/-) mice. Pretreatment of LDLr(-/-) mice with gadolinium chloride, which reduces Kupffer cell function, attenuated the hepatic leukostasis, NPS, and hepatocellular injury elicited by I/R. Similar protection against I/R was observed in LDLr(-/-) mice pretreated with antibodies directed against tumor necrosis factor-alpha, intercellular adhesion molecule-1 (ICAM-1), or P-selectin. These findings indicate that chronic hypercholesterolemia predisposes the hepatic microvasculature to the deleterious effects of I/R. Kupffer cell activation and the leukocyte adhesion receptors ICAM-1 and P-selectin appear to contribute to the exaggerated inflammatory responses observed in the postischemic liver of LDLr(-/-) mice.

Alanine Transaminase↗
PubMed2000

Heme oxygenase modulates selectin expression in different regional vascular beds.

Heme oxygenase (HO) catalyzes the degradation of heme to biliverdin, iron, and CO. The inducible isoform (HO-1) has been implicated as a modulator of the inflammatory response. HO-1 activity can be induced by hemin and inhibited with zinc protoporphyrin IX (ZnPP). Using these reagents, we assessed the possibility that HO-1 modulates the inflammatory response by altering the expression of endothelial cell adhesion molecules. Endotoxin (lipopolysaccharide, LPS)-induced expression of P- and E-selectin expression was quantified in different vascular beds of the rat using the dual radiolabeled monoclonal antibody technique. Pretreatment with hemin attenuated, whereas ZnPP treatment exacerbated, the increased selectin expression normally elicited by LPS. Biliverdin, at an equimolar dosage, was as effective as hemin in attenuating LPS-induced selectin expression in the lung, kidneys, liver, and intestines. These findings indicate that the anti-inflammatory properties of HO-1 may be related to an inhibitory action of P- and E-selectin expression in the vasculature. Biliverdin (or its metabolite, bilirubin), rather than CO, may account for this action of HO-1 on endothelial cell adhesion molecule expression.

Animals↗
PubMed2000

Role of superoxide in hemorrhagic shock-induced P-selectin expression.

Superoxide has been implicated in the regulation of endothelial cell adhesion molecule expression and the subsequent initiation of leukocyte-endothelial cell adhesion in different experimental models of inflammation. The objective of this study was to assess the contribution of oxygen radicals to P-selectin expression in a murine model of whole body ischemia-reperfusion, i.e., hemorrhage-resuscitation (H/R), with the use of different strategies that interfere with either the production (allopurinol, CD11/CD18-deficient or p47(phox)-/- mice) or accumulation [intravenous superoxide dismutase (SOD), mutant mice that overexpress SOD] of oxygen radicals. P-selectin expression was quantified in different regional vascular beds by use of the dual-radiolabeled monoclonal antibody technique. H/R elicited a significant increase in P-selectin expression in all vascular beds. This response was blunted in SOD transgenic mice and in wild-type mice receiving either intravenous SOD or the xanthine oxidase inhibitor allopurinol. Mice genetically deficient in either a subunit of NADPH oxidase or the leukocyte adhesion molecule CD11/CD18 also exhibited a reduced P-selectin expression. These results implicate superoxide, derived from both xanthine oxidase and NADPH oxidase, as mediators of the increased P-selectin expression observed in different regional vascular beds exposed to hemorrhage and retransfusion.

Animals↗
PubMed2000

Leukocyte and endothelial cell adhesion molecules in a chronic murine model of myocardial reperfusion injury.

Expression of endothelial and leukocyte cell adhesion molecules is a principal determinant of polymorphonuclear neutrophil (PMN) recruitment during inflammation. It has been demonstrated that pharmacological inhibition of these molecules can attenuate PMN influx and subsequent tissue injury. We determined the temporal expression of alpha-granule membrane protein-40 (P-selectin), endothelial leukocyte adhesion molecule 1 (E-selectin), and intercellular cell adhesion molecule 1 (ICAM-1) after coronary artery occlusion and up to 3 days of reperfusion. The expression of all of these cell adhesion molecules peaked around 24 h of reperfusion. We determined the extent to which these molecules contribute to PMN infiltration by utilizing mice deficient (-/-) in P-selectin, E-selectin, ICAM-1, and CD18. Each group underwent 30 min of in vivo, regional, left anterior descending (LAD) coronary artery ischemia and 24 h of reperfusion. PMN accumulation in the ischemic-reperfused (I/R) zone was assessed using histological techniques. Deficiencies of P-selectin, E-selectin, ICAM-1, or CD18 resulted in significant (P < 0.05) attenuation of PMN infiltration into the I/R myocardium (MI/R). In addition, P-selectin, E-selectin, ICAM-1, and CD18 -/- mice exhibited significantly (P < 0.05) smaller areas of necrosis after MI/R compared with wild-type mice. These data demonstrate that MI/R induces coronary vascular expression of P-selectin, E-selectin, and ICAM-1 in mice. Furthermore, genetic deficiency of P-selectin, E-selectin, ICAM-1, or CD18 attenuates PMN sequestration and myocardial injury after in vivo MI/R. We conclude that P-selectin, E-selectin, ICAM-1, and CD18 are involved in the pathogenesis of MI/R injury in mice.

Animals↗
PubMed2000

Role of endotoxin in the expression of endothelial selectins after cecal ligation and perforation.

The objectives of this study were to determine 1) the changes in endothelial cell adhesion molecule expression that occur in a clinically relevant model of sepsis and 2) the dependence of these changes on endotoxin [lipopolysaccharide (LPS)]. The dual radiolabeled monoclonal antibody technique was used to quantify the expression of E- and P-selectin in LPS-sensitive (C3HeB/FeJ) and LPS-insensitive (C3H/HeJ) mice that were subjected to acute peritonitis by cecal ligation and perforation (CLP). At 6 h after CLP, the expression of both E- and P-selectin was increased in the gut (mesentery, pancreas, and small and large bowel) compared with the sham-operated and/or control animals, with a more marked response noted in LPS-insensitive mice. The lung also exhibited an increased P-selectin expression in both mouse strains. An accumulation of granulocytes, assessed using tissue myeloperoxidase activity, was noted in the lung and intestine of LPS-sensitive but not LPS-insensitive mice exposed to CLP. These results indicate that the CLP model of sepsis is associated with an upregulation of endothelial selectins in the gut vasculature and that enteric LPS does not contribute to this endothelial cell activation response.

Acute Disease↗
PubMed2000

Endothelial expression of selectins during endotoxin preconditioning.

Although bacterial endotoxins [lipopolysaccharide (LPS)] can confer tissue resistance to subsequent inflammatory insults, the mechanisms that underlie this LPS-preconditioning (LPS-PC) response remain poorly defined. The dual-radiolabeled monoclonal antibody technique was used to examine whether LPS-PC alters the upregulation (protein) of E- and P-selectins after subsequent LPS challenge. In the gut of wild-type (C57BL/6J) mice, LPS-PC was associated with a reduction in E- (66%) and P-selectin (33%) expression. A similar reduction in E-selectin expression was observed in mutant mice that were genetically deficient in either the endothelial or inducible isoform of nitric oxide synthase or that overexpressed the human gene for Cu/Zn superoxide dismutase. Severe combined immunodeficient mice, genetically devoid of lymphocytes, did exhibit partial inhibition of the LPS-PC response. We conclude that 1) LPS-PC can be demonstrated for E- and P-selectins in some vascular beds (e.g., gut), 2) the mechanism(s) underlying this blunted selectin response does not include a major role for either nitric oxide and superoxide, and 3) circulating lymphocytes may contribute to the LPS-PC response.

Animals↗
PubMed2000

Endothelial cells exposed to anoxia/reoxygenation are hyperadhesive to T-lymphocytes: kinetics and molecular mechanisms.

OBJECTIVE: The objectives of this study were to 1) determine the time-course of T-lymphocyte adhesion to monolayers of human umbilical vein endothelial cell (HUVEC) that were exposed to 60 min of anoxia followed by 24 h of reoxygenation, and 2) define the mechanisms responsible for the hyperadhesivity of postanoxic HUVEC to human T-lymphocytes. METHODS: Human peripheral blood mononuclear leukocytes were isolated from heparinized peripheral blood. T-lymphocytes were obtained by negative selection using a MACS column. HUVEC monolayers were exposed to anoxia/reoxygenation (A/R), and then reacted with 51Cr -labeled T-lymphocytes in adhesion assays. RESULTS: A/R leads to an increased adhesion of T-lymphocytes to HUVEC monolayers, with peak responses occurring at 8 h after reoxygenation. This adhesion response was largely attributed to the CD4+ T-cell subset. The hyperadhesivity of A/R-exposed HUVEC was inhibited by monoclonal antibodies directed against either LFA-1, VLA-4, ICAM-1, or VCAM-1, indicating a contribution of these adhesion molecules and their ligands. Moreover, T-cell hyperadhesivity was attenuated by anti- IL-8. consistent with a role for this chemokine in the adhesion response. Protein synthesis inhibitors (actinomycin D and cycloheximide) as well as chemical inhibitors of (and binding ds-oligonucleotides to) NFkappaB and AP-1 significantly attenuated the A/R-induced T-lymphocyte adhesion responses. The kinetics of VCAM-1 on post-anoxic HUVEC correlated with the T-lymphocyte adhesion response. CONCLUSIONS: A/R elicits a T-lymphocyte-endothelial cell adhesion response that involves transcription-dependent surface expression of VCAM-1.

Antibodies, Monoclonal↗
PubMed2000

Expression of endothelial cell adhesion molecules in neovascularized tissue.

OBJECTIVE: Recent studies indicate that endothelial cells of newly formed blood vessels are activated and exhibit a distinct phenotype that may influence the responses of these microvessels to an inflammatory stimulus. The objective of this study was to compare the basal and cytokine-stimulated expression of endothelial cell adhesion molecules in neovascularized tissue to normal (nonproliferating) vascular beds. METHODS: The expression of P- and E-selectin. VCAM-1, ICAM-1, ICAM-2, and PECAM-1 was measured, using the dual radiolabeled mAb technique, in subcutaneously implanted (for 10-15 days) polyurethane sponges, skin, heart, lung, and intestine of male C57BL/6 mlice (background). RESULTS: Basal values of PECAM-1 and ICAM-2 revealed a low vascular density in the implanted sponge matrices that is comparable to skin. When normalized for vascular surface area (PECAM-1 or ICAM-1 expression), the basal level of E- and P-selectin expression was highest in neovascularized sponge and skin. TNF-alpha elicited an increased expression of all endothelial CAMs, except PECAM-1 and ICAM-2, but the responses were blunted in sponge and skin, relative to other vascular beds. CONCLUSIONS: These findings indicate that endothelial cells in newly formed blood vessels exhibit a pattern of basal and cytokine-induced expression of certain adhesion glycoproteins that is similar to nonproliferating cutaneous vessels.

Animals↗
PubMed2000

Persantine attenuates hemorrhagic shock-induced P-selectin expression.

Ischemia/reperfusion (I/R), a phenomenon that is associated with conditions such as organ transplantation, trauma, vascular disease, and stroke, involves the recruitment of activated and adherent leukocytes that subsequently mediate tissue injury. Endothelial cell adhesion molecules such as P-selectin mediate I/R-induced leukocyte recruitment and allow the adherent leukocytes to damage the vascular wall and parenchymal cells. This study examines the influence of dypiridamole (persantine) on hemorrhagic shock (H/S)-induced P-selectin expression. H/S was induced in C57BL/6 mice by withdrawing blood to drop the mean arterial blood pressure to 30 to 35 mm Hg for 45 minutes. The mice were resuscitated by infusing the shed blood and Ringer's lactate (50% shed blood volume). In vivo P-selectin expression was determined using a dual monoclonal antibody technique in the heart, lung, liver, kidneys, stomach, small bowel, and colon of a control group, a hemorrhagic shock group, and a hemorrhagic shock group that was pretreated with Persantine (Boehringer, Ingelheim, Ingelheim, Germany). H/S significantly (P < 0.01) increased P-selectin expression in all regional vascular beds of untreated mice. Persantine treatment largely prevented the H/S-induced P-selectin expression in the same vascular beds. Persantine significantly attenuates the upregulation of P-selectin in the hemorrhagic shock model.

Adenosine↗
PubMed1999

Influence of dose-rate on inflammatory damage and adhesion molecule expression after abdominal radiation in the rat.

PURPOSE: The goal of this study was to assess the effects of two clinically relevant radiation dose-rates on endothelial adhesion molecule expression, inflammatory response, and microvascular dysfunction. METHODS AND MATERIALS: Rats were irradiated with 10 Gy at low (0.9 Gy/min) or high (3 Gy/min) dose-rates. Control animals received sham irradiation. Leukocyte rolling, adhesion, emigration, and microvascular permeability were assessed in mesenteric venules by intravital microscopy 6 hours after irradiation. P-selectin and intercellular adhesion molecule-1 (ICAM-1) expression were measured using radiolabeled monoclonal antibodies. RESULTS: Low dose-rate (LDR) abdominal irradiation increased leukocyte adhesion compared with sham-irradiated animals, whereas high dose-rate (HDR) irradiation resulted in enhanced leukocyte rolling, adhesion, and emigration, compared with the LDR or with sham-irradiated rats. Both dose-rates increased microvascular permeability, although this effect was significantly greater after radiation with the high (8-fold) than the low (5-fold) dose-rate. HDR radiation induced significantly larger increments in P-selectin expression in splanchnic organs than LDR, whereas in most organs ICAM-1 expression was only upregulated by the HDR. Blockade of ICAM-1, but not P-selectin, abrogated leukocyte adhesion at both dose-rates. CONCLUSIONS: The magnitude of upregulation of endothelial adhesion molecules, leukocyte recruitment, and endothelial barrier dysfunction elicited by radiation therapy is dependent on the dose-rate at which the radiation is delivered.

Abdomen↗
PubMed1999

Molecular mechanisms underlying IL-4-induced leukocyte recruitment in vivo: a critical role for the alpha 4 integrin.

IL-4 is known to induce recruitment of eosinophils and mononuclear leukocytes. In vitro this occurs in part by selective expression of VCAM-1, the ligand for the alpha 4 integrin. The objective of this study was to determine the molecular mechanisms that underlie IL-4-induced leukocyte recruitment in vivo. Mice received an intrascrotal injection of IL-4 (100 ng). Twenty-four hours later, leukocyte rolling, adhesion, and emigration in cremasteric postcapillary venules were examined via intravital microscopy, and expression of VCAM-1 and P- and E-selectin was quantitated using a radiolabeled mAb technique. IL-4 increased VCAM-1 expression, but P-selectin and E-selectin remained at constitutive levels. IL-4 induced significant increases in leukocyte adhesion and emigration, with 50% of the emigrated cells being eosinophils and the remainder being mononuclear leukocytes. Leukocyte rolling in IL-4-treated mice was >95% inhibitable using an anti-P-selectin Ab. However, IL-4-induced leukocyte recruitment was unaltered in mice treated chronically with P-selectin Ab or mice deficient in either P-selectin or P- and E-selectin, suggesting that the residual rolling supported all of the IL-4-induced recruitment. In IL-4-treated mice following P-selectin blockade, tethering and rolling were not dependent on L-selectin, but were abolished by alpha 4 integrin blockade. These findings show that the alpha 4 integrin can initiate leukocyte-endothelial cell interactions in the absence of selectins under shear conditions in vivo, and that the absence of selectins does not affect recruitment of eosinophils and mononuclear cells to IL-4-treated tissue.

Animals↗
PubMed1999

Molecular mechanisms of neutrophil-endothelial cell adhesion induced by redox imbalance.

Previous studies have implicated a role for intracellular thiols in the activation of nuclear factor-kappaB and transcriptional regulation of endothelial cell adhesion molecules. This study was designed to determine whether changes in endothelial cell glutathione (GSH) or oxidized glutathione (GSSG) can alter neutrophil adhesivity and to define the molecular mechanism that underlies this GSSG/GSH-induced adhesion response. Treatment of human umbilical vein endothelial cell (HUVEC) monolayers for 6 hours with 0.2 mmol/L diamide and 1 mmol/L buthionine sulfoximine (BSO) decreased GSH levels and increased the ratio of GSSG to GSH without cell toxicity. These redox changes are similar to those observed with anoxia/reoxygenation. Diamide plus BSO-induced thiol/disulfide imbalance was associated with a biphasic increase in neutrophil adhesion to HUVECs with peak responses observed at 15 minutes (phase 1) and 240 minutes (phase 2). N-Acetylcysteine treatment attenuated neutrophil adhesion in both phases, which indicated a role for GSH in the adhesion responses. Interestingly, phase 1 adhesion was inversely correlated with GSH levels but not with the GSSG/GSH ratio, whereas phase 2 neutrophil adhesion was positively correlated with GSSG/GSH ratio but not with GSH levels. Intercellular adhesion molecule-1 and P-selectin-specific monoclonal antibodies attenuated the increased neutrophil adhesion during both phases, whereas an anti-E-selectin monoclonal antibody also attenuated the phase 2 response. Pretreatment with actinomycin D and cycloheximide or with competing ds-oligonucleotides that contained nuclear factor-kappaB or activator protein-1 cognate DNA sequences significantly attenuated the phase 2 response, which implicated a role for de novo protein synthesis. Surface expression of intercellular adhesion molecule-1, P-selectin, and E-selectin on HUVECs correlated with the phase 1 and 2 neutrophil adhesion responses. This study demonstrates that changes in endothelial cell GSSG/GSH cause transcription-independent and transcription-dependent surface expression of different endothelial cell adhesion molecules, which leads to a 2-phase neutrophil-endothelial adhesion response.

Cell Adhesion↗
PubMed1999

Varying roles of E-selectin and P-selectin in different microvascular beds in response to antigen.

Expression of E-selectin and P-selectin is critical in the effector phase of leukocyte recruitment in response to Ag. Whether their relative roles differ between tissues in response to the same Ag is unknown. In this study, a type I hypersensitivity response was elicited in C57BL/6 mice by systemic sensitization with OVA. Following local Ag challenge, endothelial selectin expression was examined in the skin and cremaster muscle microvasculature using a dual-radiolabeled mAb technique. Next, the dermal and muscle microcirculations were visualized using intravital microscopy to establish roles for P-selectin and/or E-selectin. In untreated mice, leukocyte recruitment in both skin and skeletal muscle was mediated entirely by P-selectin. Following Ag challenge, leukocyte rolling flux and adhesion were dramatically increased and leukocyte rolling velocity was unchanged in muscle. Only P-selectin expression increased in muscle, and leukocyte recruitment was entirely dependent upon this selectin. In contrast, in Ag-challenged skin, leukocyte rolling flux did not increase, but rolling velocity dropped profoundly. In skin, only E-selectin expression increased, and blockade of either E-selectin or P-selectin had minimal effect on either rolling flux or rolling velocity. Blockade of both selectins reduced rolling flux by 80% and increased rolling velocity sevenfold. These data highlight striking differences in expression of the endothelial selectins in separate microvascular beds in response to the same stimulus and demonstrate that these differences underlie very different patterns of leukocyte recruitment. The data underscore the importance of studying individual microvascular beds to understand tissue-specific leukocyte recruitment in vivo.

Animals↗
PubMed1999

Route of nutrition influences intercellular adhesion molecule-1 expression and neutrophil accumulation in intestine.

HYPOTHESIS: The levels of intestinal interleukin 10 and interleukin 4, inhibitors of intercellular adhesion molecule-1 (ICAM-1) expression, decline with total parenteral nutrition (TPN). These cytokine changes induced by lack of enteral nutrition may increase ICAM-1 expression, resulting in polymorphonuclear neutrophil accumulation in intestine. DESIGN: Prospective randomized experimental trials. SETTING: Laboratory. MATERIALS: Male mice. INTERVENTIONS: Sixty-three mice were randomized to chow, intravenous TPN, or intragastric TPN. MAIN OUTCOME MEASURES: Experiment 1: After diet manipulation, iodine 125-labeled anti-ICAM-1 antibody and iodine 131-labeled nonbinding antibody were injected to quantify ICAM-1 expression on endothelial cells in the lung, liver, kidney, and small intestine. Measurement of myeloperoxidase was used to quantify polymorphonuclear neutrophil accumulation in the organs. Experiment 2: Intestine was harvested for both ICAM-1 and myeloperoxidase levels after chow refeeding of mice in the intravenous TPN group. RESULTS: In experiment 1, uninjured mice fed intravenous TPN showed significantly increased intestinal ICAM-1 expression and polymorphonuclear neutrophil accumulation with no significant changes in the lung, liver, or kidney. No changes occurred in mice fed chow or intragastric TPN. In experiment 2, reinstitution of enteral feeding returned intestinal ICAM-1 and myeloperoxidase levels to normal. CONCLUSION: Gut changes associated with lack of enteral feeding induce endothelial changes and an immunologic response, which may influence subsequent responses to injury.

Animals↗