Arginine and immunonutrition: a reevaluation.
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Animals↗
Biomedical subjects
A Barbul
Publications and source records attributed to A Barbul.
Immunonutrition comes of age.
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Critical Care↗
Role of arginine in immunonutrition.
Arginine plays an important role in many physiologic and biologic processes beyond its role as a protein-incorporated amino acid. Dietary supplementation of arginine can enhance wound healing, regulate endocrine activity and potentiate immune activity. Under normal unstressed conditions the arginine requirement of adult humans is fulfilled by endogenous sources, however this is compromised during times of stress, especially in critical illness. These finding have led to use of arginine supplementation as part of an immune-enhancing dietary regimen to help combat the immune suppression seen in such patients. Though the results from studies examining the use of this type of immunonutrition in critically ill patients are far from definitive, they are promising that this mode of therapy may be of some advantage. A better understanding of the in vivo biology of arginine and its metabolism is necessary to truly define a benefit from arginine supplementation.
Adult↗
Acute abdomen with colonic necrosis induced by Kayexalate-sorbitol.
Colonic necrosis is an unusual complication after treatment of hyperkalemia with sodium polystyrene sulfonate (SPS, Kayexalate) in sorbitol. To increase awareness of this complication, we report a case of necrosis of the transverse colon in a patient given oral and rectal SPS-sorbitol for hyperkalemia. Colonic necrosis was manifested as an acute abdomen within 24 hours of initial administration. Prompt surgical resection of the necrotic transverse colon permitted rapid recovery of bowel function. Although SPS crystals are seen microscopically in the necrotic bowel, experimental evidence implicates the sorbitol component of the SPS-sorbitol in the pathogenesis of colonic necrosis. A high index of suspicion for the unusual complication of colonic necrosis after oral or rectal administration of SPS-sorbitol may allow prompt recognition and surgical cure.
Abdomen, Acute↗
Deoxygenation and elevation of intracellular magnesium induce tyrosine phosphorylation of band 3 in human erythrocytes.
Deoxygenation increases the level of tyrosine phosphorylation of band 3 by approximately 25% in human red blood cells (RBCs), as determined by Western blotting. The effect is much more pronounced in osmotically shrunken RBCs or in the presence of vanadate. When the rise in intracellular free Mg2+ concentration in deoxygenated RBCs is simulated via clamping of the intracellular magnesium in oxygenated RBCs by ionomycin, band 3 phosphorylation is elevated by up to 10-fold. Phosphorylated band 3 is preferentially retained by RBC skeletons, after mild extraction with Triton X-100. Elevation of intracellular free Mg2+ leads to band 3 phosphorylation and is accompanied by rigidification of the membrane skeleton as determined by analysis of RBC membrane mechanical fluctuations. These findings suggest that the visco-elastic properties of human erythrocytes may be regulated by band 3 tyrosine phosphorylation.
Anion Exchange Protein 1, Erythrocyte↗
Arginine and nutrition in renal disease.
The physiological significance of arginine metabolism extends far beyond its incorporation as an amino acid into proteins. In addition to its effects when administered as a dietary supplement, the end-products of arginine metabolism by the enzymes arginase, arginine decarboxylase (ADC), and nitric oxide synthase (NOS) have been shown to play roles in wound healing, immune response, tumor biology, and the regulation of inflammation. These properties make arginine metabolism a significant concern in defining and, likely, treating renal disease.
Arginine↗
Detection of movement at the erythrocyte's edge by scanning phase contrast microscopy.
A time-dependent set of line scans across an erythrocyte was recorded by a phase contrast laser scanning microscope. A method for edge detection, based on a two-stage fitting procedure of the theoretical intensity distribution in a line scan of phase contrast image to the experimental one, is suggested. Time-resolved fluctuations of the human erythrocyte's edge were obtained, employing this method. The same procedure was carried out for a metallic strip yielding a test for the background noise level. The suggested method was applied in examining the effect of chemical crosslinking and thiol reduction on cell membrane fluctuations of human erythrocytes.
Cell Movement↗
Inhibition of nitric oxide synthesis in wounds: pharmacology and effect on accumulation of collagen in wounds in mice.
OBJECTIVE: To investigate the effect of systemic inhibition of nitric oxide (NO) synthesis in wounds on collagen accumulation. DESIGN: Randomised experimental study. SETTING: Teaching hospital, USA. MATERIAL: 240 Balb/C mice divided into groups of 10 animals each. INTERVENTIONS: Polyvinyl alcohol sponges were inserted subcutaneously through a dorsal skin incision. Beginning on the day of wounding, N omega-nitro-L-arginine-methylester (L-NAME), NG-L-monomethyl-arginine (L-NMMA), aminoguanidine hemisulphate (AGU), and S-methyl isothiouronium (MITU) were given orally or intraperitoneally. The mice were killed 10 days later. MAIN OUTCOME MEASURES: Nitrite and nitrate concentrations, both stable end products of NO, were measured in wound fluid. Sponge hydroxyproline content was assayed as an index of reparative collagen deposition. RESULTS: NOS inhibitors given orally in the drinking water or by daily intraperitoneal injection had no effect on wound nitrite/nitrate concentrations or deposition of collagen in wounds. When given continuously through intraperitoneally-placed osmotic pumps, AGU (500 mg/kg/day) (p < 0.001) and MITU (p < 0.01) significantly reduced wound fluid nitrite/nitrate concentrations in a dose dependent manner. Inhibition of wound nitric oxide synthase by 500 mg AGU/kg/day and 100 mg MITU/kg/day was paralleled by lowered accumulation of collagen in wounds (p < 0.01). CONCLUSION: NO is beneficial in wound healing.
Analysis of Variance↗
Enhanced collagen accumulation following direct transfection of the inducible nitric oxide synthase gene in cutaneous wounds.
Inducible nitric oxide synthase (iNOS) is expressed during cutaneous wound repair. Mounting evidence suggests that wound nitric oxide (NO) augments collagen accumulation. We hypothesized that in vivo transfection of wound cells with the iNOS gene would increase physiological wound NO levels and thus augment collagen accumulation. Polyvinyl alcohol sponges were instilled with a mammalian expression plasmid (pMP6) containing either the chloramphenicol acetyl transferase (CAT) reporter or murine iNOS gene driven by a CMV immediate-early promoter. Plasmid DNA was injected alone or in complex with cationic liposomes, and the sponges were placed subcutaneously in male Sprague-Dawley rats which had received a longitudinal dorsal midline incision. Animals were sacrificed at different time points post-wounding and the sponges assayed for CAT activity, transfected iNOS mRNA, total nitrate and nitrite concentration (NOx) (as an index of wound NO synthesis), and hydroxyproline content (as an index of sponge collagen accumulation). The results demonstrate that wound cells were more efficiently transfected by naked DNA than by liposome mediated transfection and that maximal expression of both iNOS and CAT occurred at 48 hrs with a rapid decline after this time point. After 7 days, iNOS transfected sponges had accumulated significantly more collagen than those transfected with CAT. We conclude that cutaneous wounds can be successfully transfected by direct injection of naked DNA and that increased iNOS expression precedes an increase in collagen synthesis.
Animals↗
Lymphocyte function in wound healing and following injury.
BACKGROUND: Injury activates a cascade of local and systemic immune responses. METHODS: A literature review was undertaken of lymphocyte function in wound healing and following injury. RESULTS: Lymphocytes are not required for the initiation of wound healing, but an intact cellular immune response is essential for a normal outcome of tissue repair. Injury affects lymphocyte immune mechanisms leading to generalized immunosuppression which, in turn, increases host susceptibility to infection and sepsis. Although the exact origin of post-traumatic immunosuppression remains unknown, stress hormones and immunosuppressive factors, such as inflammatory cytokines, prostaglandin E2 and nitric oxide, affect lymphocyte function adversely. Post-traumatic impairment of T lymphocyte immune function is reflected in decreased lymphocyte numbers, as well as altered T cell phenotype and activity. Antibody-producing B lymphocytes are variably affected by injury, probably secondary to alterations of T lymphocyte function, as a result of their close interaction with helper T cells. Therapeutic modulation of the host immune response may include non-specific and specific interventions to improve overall defence mechanisms. CONCLUSION: Early resuscitation to restore lymphocyte function after injury is important for tissue repair and the prevention of immunosuppression.
Animals↗
Modulation of inflammation and immunity by arginine supplements.
Arginine holds a key position in the cellular functions and interactions that occur during inflammation and immune responses. The competition for arginine as a substrate between nitric oxide synthase and arginase appears to be at the core of the regulation of the inflammatory process. This review examines some of the recently defined effects of arginine on various inflammatory processes and immune cell functions.
Animals↗
Metalloproteinase inhibitors and wound healing: a novel enhancer of wound strength.
BACKGROUND: Wound strength is a balance between collagen synthesis and degradation. The role of collagen breakdown in wound healing is still not well understood. We investigated the role of collagenases (metalloproteinases [MMPs]) in wound healing in using GM6001, a novel inhibitor of MMPs. METHODS: We used the dorsal skin incision model with implantation of polyvinyl alcohol sponges. Twenty male Sprague-Dawley rats were randomly assigned to receive either GM6001 (10 mg/kg body weight) or 2 mL saline subcutaneously. Ten days after operation the animals were killed and fresh wound breaking strength, scar and sponge hydroxyproline content, and collagen type I gene expression in sponges were assayed. In addition, the inflammatory response and the wound fluid cytokine (tumor necrosis factor-alpha [TNF-alpha] and transforming growth factor-beta 1 [TGF-beta 1]) profile were studied. RESULTS: GM6001 significantly increased wound strength (422 +/- 59 vs 302 +/- 33 g, P < .05), whereas scar collagen content did not differ. In the sponge granulomas the inflammatory infiltrate, the collagen content, and the collagen type I gene expression were all significantly decreased by GM6001. CONCLUSIONS: Inhibition of MMP activity during acute wound healing enhances wound strength even though new collagen synthesis and the inflammatory response are significantly decreased. This could be achieved by decreasing collagen turnover or increasing collagen maturation and crosslinking, or both.
Animals↗
Nitric oxide metabolism in wounds.
Arginine can be metabolized in wounds to nitric oxide and citrulline by nitric oxide synthase or to urea and ornithine by arginase. We investigated the expression of these arginine metabolic pathways over a 3-week period. Groups of 8-10 male Balb/C mice underwent a dorsal skin incision and subcutaneous polyvinyl alcohol sponge implantation. The animals were sacrificed at various times, and sponges were harvested to obtain wound fluid and wound cells. Cells or whole sponges were incubated with L-[2,3-(3)H]arginine, with or without N(G)-L-monomethyl-arginine (NMMA, a competitive inhibitor of nitric oxide synthase). Nitrite and nitrate (both stable end products of nitric oxide metabolism) and amino acids were measured in wound fluid and wound cell culture supernatants. Increasing concentrations of nitrite and nitrate were noted in wound fluid and in whole sponge cultures until the second week postwounding, indicating sustained wound nitric oxide synthesis. In wound fluid arginine levels were undetectable at all times, suggesting sustained utilization. Wound fluid citrulline levels showed an early peak and then a gradual decrease, suggesting that recycling for continued nitric oxide production may occur. Wound fluid ornithine levels increased until Day 10 and remained elevated, indicative of continued arginase activity. In vitro production of nitrite/nitrate and citrulline by cells and whole sponges was inhibitable by NMMA. Inducible nitric oxide synthase expression was confirmed by immunoblotting, while immunohistochemistry demonstrated that macrophages are a major source of wound nitric oxide. The data show that nitric oxide synthesis occurs for prolonged periods after injury and macrophages appear to be a major cellular source.
Animals↗
Nitric oxide, an autocrine regulator of wound fibroblast synthetic function.
Nitric oxide (NO) is synthesized in wounds, but its exact role and cellular source are not known. Wound fibroblasts (WF) are phenotypically characterized by increased collagen synthesis and contractility. We hypothesized that WF may be also phenotypically altered during wound healing to synthesize NO. WF were isolated from polyvinyl alcohol sponges implanted in male Lewis rats and harvested 10 days later. Proliferation in response to 10% fetal bovine serum was assessed by [3H]thymidine incorporation in a microculture system. A fibroblast-populated collagen lattice was used for assaying contractility. Collagen synthesis was determined by measuring the collagenase-sensitive fraction of protein-incorporated [3H]proline. Fibroblasts were incubated in the presence or the absence of 0.5 mM S-methyl-isothio-uronium or 0.5 mM N-monomethyl-L-arginine, both competitive inhibitors of NO synthase. WF spontaneously synthesize and release NO (4.60 +/- 0.29 nmol nitrite/microg DNA/48 h). Normal dermal fibroblasts do not synthesize NO. WF NO synthesis was limited to the first and second passages postharvest and was inhibitable by S-methyl-isothio-uronium (96%) and N-monomethyl-L-arginine (84%). In vivo iNOS expression by WF was confirmed by in situ hybridization and immunohistochemistry. Inhibition of endogenous NO synthesis had no effect on fibroblast proliferation. However, fibroblast-mediated collagen contraction was enhanced (p < 0.01), and collagen synthesis was significantly decreased (p < 0.05) by inhibiting NO synthase. The data show that WF are phenotypically altered during the healing process to synthesize NO, which, in turn, regulates their collagen synthetic and contractile activities.
Animals↗
Sepsis impairs anastomotic collagen gene expression and synthesis: a possible role for nitric oxide.
Although intra-abdominal sepsis is known to impair colon healing by inhibiting anastomotic collagen synthesis, the effect of systemic sepsis on this process is unknown. Endotoxins and cytokines associated with sepsis induce nitric oxide synthesis both systemically and locally within colonic tissue. We hypothesized that systemic sepsis impairs colonic healing and examined a possible correlation with nitric oxide expression. Male Sprague-Dawley rats received intraperitoneal injections of either saline (sham group) or Escherichia coli endotoxin (lipopolysaccharide 1 mg/100 g body weight) at Times -24 and -12 hr (LPS group). All animals underwent laparotomy and left colonic anastomosis at Time 0. At 24 and 96 hr postlaparotomy rats were sacrificed, the anastomoses excised, and [3H]-proline incorporation into protein measured as an index of total new protein synthesis (TNP). Digestion with purified collagenase yielded incorporation into the collagen fraction (CDP). Additional sham and LPS-treated rats were sacrificed at 24, 72, and 120 hr, the anastomoses excised, and nitric oxide synthase activity in the tissue measured by the conversion of [3H]-arginine to [3H]citrulline in an ex vivo culture system. Finally, sham and LPS rats were sacrificed at 120 hr for measurement of colon anastomotic bursting pressure. Systemic sepsis significantly impaired new collagen synthesis in anastomotic tissue at 24 hr compared to control samples (P < 0.02). No difference was noted at 96 hr. TNP synthesis was similar in both groups at 24 or 96 hr. Northern blot analysis confirmed a significant decrease in Type I and Type III collagen mRNA expression at 24 hr in septic rats. Anastomotic bursting pressure was also decreased in the septic group (P < 0.003). Sepsis elevated nitric oxide synthase activity in anastomotic tissue 24 hr postanastomosis, when compared to sham tissue (P < 0.0001). These data suggest that systemic endotoxin induces nitric oxide synthesis at the anastomotic site. The simultaneous dysregulation of collagen gene expression and synthesis with decreased anastomotic strength suggests a possible regulatory role for nitric oxide in gastrointestinal healing.
Anastomosis, Surgical↗
Diabetes-impaired healing and reduced wound nitric oxide synthesis: a possible pathophysiologic correlation.
BACKGROUND: Nitric oxide (NO) is synthesized in wounds, but its role in the healing process is not fully understood. The inhibition of NO production during wound healing is accompanied by decreased wound reparative collagen deposition. To further define the role of NO in reparative collagen accumulation, we studied its production during diabetes-induced wound healing impairment. METHODS: Male Sprague-Dawley rats (290 to 310 gm) were rendered diabetic by intraperitoneal streptozotocin administration. Seven days after induction of diabetes (blood glucose greater than 300 mg/dl), the rats underwent dorsal skin incision and subcutaneous implantation of polyvinyl alcohol sponges. Beginning on the day of wounding, 21 diabetic animals were treated with 3 units/day insulin via intraperitoneally implanted miniosmotic pumps. Ten days after injury, wound breaking strength was determined, and wound collagen accumulation and types I and III collagen gene expression were measured in subcutaneously implanted polyvinyl alcohol sponges. NO-synthesis, as measured by nitrite/nitrate accumulation, was determined in wound fluid and in supernatants of wound cell cultures. RESULTS: Streptozotocin-induced diabetes markedly impaired wound breaking strength and collagen deposition. A parallel decrease occurred in wound NO synthesis as reflected by decreased nitrite/nitrate concentration in wound fluid and in diminished ex vivo NO production by wound cells. Insulin treatment partially but significantly improved wound mechanical strength (p < 0.01) and collagen accumulation (p < 0.001). Decreased wound NO accumulation and ex vivo NO production by wound cells were also partially restored by insulin treatment. CONCLUSIONS: Impaired diabetic wound healing is paralleled by decreased wound NO synthesis, supporting the hypothesis that NO plays a significant role in wound reparative collagen accumulation.
Animals↗
General principles of wound healing.
Wound healing is a complex process involving different biologic and immunologic systems. Despite improvements in diagnostics and therapy, wound failures remain a clinical problem. The approach to a nonhealed wound is an interdisciplinary challenge that should not be underestimated. Better understanding of the complex wound-healing cascade helps our approach to wound healing and its possible failure. Manipulations of the involved immunologic features offer future therapeutic strategies.
Cell Division↗