Biomedical subjects

Axel M Gressner

Publications and source records attributed to Axel M Gressner.

At least 37 records · Page 2Linked to original sources

PubMed2005

Cryopreservation of hepatic stellate cells.

BACKGROUND/AIMS: Isolated rat hepatic stellate cells (HSC) are taken as a valuable in vitro model to study hepatic fibrogenesis, biotransformation of pharmaceutics, gene expression, transcription factors controlling HSC behaviour, and for the establishment of long-term cultures. Consequently, methods for the isolation and maintenance of HSC cultures are well documented. However, there is ongoing controversial discussion directed on the existence and cellular origin of different HSC subpopulations. Thus, there is a continuing need for developing methods allowing the exchange of HSC isolates between different laboratories. A practical solution to this problem is cryopreservation and banking of HSC. METHODS: We here describe for the first time the successful establishment of a methodology for long-term cryopreservation and recovery of primary, non-activated HSC from rats. We have optimised critical factors for HSC-banking including prefreeze processing, freezing rate, freezing medium, final cooling temperature, and thawing conditions. We found that DMSO gave far superior attachment and viability on thawing than other cryoprotectants. The viability and cellular characteristics of thawed cells was comparatively analysed by light- and electron microscopic analysis, proliferation assay, Oil Red O-staining, apoptosis testing, and evaluation of marker proteins for fibrogenic activities. RESULTS: In summary, our data reveal no significant differences in the biochemical and cellular properties between cryopreserved/thawed and freshly isolated HSC. CONCLUSIONS: According to these results, we suggest that cryoprotected HSC retain functional integrity thereby allowing banking and comfortable exchange of these cells between different laboratories.

Animals↗

PubMed2005

Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans.

Fibrogenesis or scarring of the liver is a common consequence of all chronic liver diseases. Here we refine a quantitative trait locus that confers susceptibility to hepatic fibrosis by in silico mapping and show, using congenic mice and transgenesis with recombined artificial chromosomes, that the gene Hc (encoding complement factor C5) underlies this locus. Small molecule inhibitors of the C5a receptor had antifibrotic effects in vivo, and common haplotype-tagging polymorphisms of the human gene C5 were associated with advanced fibrosis in chronic hepatitis C virus infection. Thus, the mouse quantitative trait gene led to the identification of an unknown gene underlying human susceptibility to liver fibrosis, supporting the idea that C5 has a causal role in fibrogenesis across species.

Animals↗

PubMed2005

Abrogation of transforming growth factor-beta signaling by SMAD7 inhibits collagen gel contraction of human dermal fibroblasts.

Human fibroproliferative disorders like hypertrophic scarring of the skin are characterized by increased contractility and excess extracellular matrix synthesis. A beneficial role of transforming growth factor (TGF)-beta in wound healing was proposed; however, chronic stimulation by this cytokine leads to fibrosis. In the present report, the intracellular TGF-beta signaling in fibroblasts derived from hypertrophic scars and normal skin was examined. In an attempt to intervene in profibrogenic TGF-beta functions, ectopic expression of Smad7 or dominant negative Smads3/4 completely inhibited contractility of scar-derived and normal fibroblasts after suspension in collagen gels. Both cell types displayed constitutive Smad2/3 phosphorylation and (CAGA)9-MLP-Luc activity with expression and phosphorylation of Smad3 being predominant in hypertrophic scar-derived fibroblasts. Down-regulation of intrinsic signaling with various TGF-beta antagonists, e.g. soluble TGF-beta receptor, latency-associated peptide, and anti-TGF-beta1 antibodies, confirms autocrine TGF-beta stimulation of both cell populations. Further, Smad7 expression inhibited alpha1 (I) collagen and alpha-smooth muscle actin expression. In summary, our data indicate that autocrine TGF-beta/Smad signaling is involved in contractility and matrix gene expression of fibroblasts from normal and hypertrophic scars. Smad7 inhibits these processes and may exert beneficial effects on excessive scar formation.

Actins↗

PubMed2005

Patients with acute on chronic liver failure display "sepsis-like" immune paralysis.

BACKGROUND/AIMS: Cellular immune depression is linked to high mortality in sepsis, but has yet to be systematically analysed in liver cirrhosis. The aim of the present study was to directly compare functional immune parameters in patients with acute on chronic liver failure (ACLF), severe sepsis, and non-decompensated cirrhosis. METHODS: Patients with ACLF (n=27) were investigated at admission to a medical ICU. Patients with stable liver cirrhosis (n=24) and severe sepsis (n=31) served as control groups. In all subjects, serum levels of IL-6 and IL-10, ex vivo production of TNF-alpha in a whole blood assay, and monocyte surface HLA-DR expression were determined. RESULTS: In patients with ACLF or sepsis, ex vivo TNF-alpha production and HLA-DR expression were severely decreased compared to subjects with stable cirrhosis (both P<0.001). Contrary, IL-6 levels were highest in septic patients, followed by subjects with ACLF and cirrhotic patients (both P<0.05). Immune dysfunction in ACLF was independent of aetiology of liver cirrhosis and associated with high mortality. CONCLUSIONS: Patients with ACLF and severe sepsis show a similar degree of cellular immune depression. The reduced cellular immune function in subjects with ACLF might contribute to the increased infectious morbidity of these patients and provide a rational basis for prevention strategies.

Adult↗

PubMed2005

Transdifferentiation-dependent expression of alpha-SMA in hepatic stellate cells does not involve TGF-beta pathways leading to coinduction of collagen type I and thrombospondin-2.

Hepatic stellate cells (HSC) cultured on plastic spontaneously transdifferentiate to a myofibroblast-like cell type (MFB). This model system of hepatic fibrogenesis is characterized by phenotypic changes of the cells and increased matrix synthesis. Here, we analyzed if transdifferentiation-dependent induction of ECM components, e.g., collagen type I and thrombospondin-2 (TSP-2), and phenotypic changes are coregulated events and if both processes are mediated via TGF-beta pathway(s). Blocking the TGF-beta-dependent p38 MAPK pathway in HSC with the specific inhibitor SB203580 strongly reduces collagen I and TSP-2 mRNA expression without inhibiting upregulation of the typical MFB-marker, alpha-smooth-muscle actin (alpha-SMA). Similarly, interference with the Smad2/3/4 pathway using dexamethasone also heavily decreased expression of collagen type I and TSP-2 whereas transdifferentiation of HSC to the typical morphology of MFB with loss of fat droplets and increasing alpha-SMA was unchanged. Further, p38 MAPK mediated induction of collagen I and TSP-2 expression by TGF-beta1 was still achieved in the presence of dexamethasone, showing that dexamethasone does not block p38 while it delays Smad2 phosphorylation and antagonizes stimulation of a Smad3/Smad4 dependent TGF-beta reporter construct. Interestingly, in contrast to SB203580 and dexamethasone, overexpression of the TGF-beta antagonist Smad7 reduced ECM expression and simultaneously inhibited morphologic transdifferentiation, indicating that Smad7 fulfills additional features in HSC. In conclusion, our data show that phenotypic changes of transdifferentiating HSC and induction of matrix synthesis are independent processes, the latter being stimulated by both, Smad dependent and MAPK dependent TGF-beta signaling.

Actins↗

PubMed2005

Characterization of intracellular pathways leading to coinduction of thrombospondin-1 and TGF-beta1 expression in rat hepatic stellate cells.

Accumulating evidence has identified Thrombospondin (TSP)-1 as important activator of latent TGF-beta. Since little is known about signal transduction pathways regulating TSP expression in liver, we investigated cytokine-mediated upregulation of TSP-1 and TGF-beta1 in primary rat hepatic stellate cells (HSC). PDGF-BB and TNF-a rapidly coinduce mRNA levels of TSP-1 and TGF-beta1. Interestingly, blockade of basal Erk activity by synthetic Erk-binding peptides also leads to strong induction of both mRNA transcripts in non-stimulated cells. We show that PDGF-BB induces TSP-1 and TGF-beta1 via the src kinase pathway whereas TNF-a utilizes the MAPK/Erk pathway. However, especially TSP-1 induction by both cytokines involves a pathway, which depends to a certain extent on PI3 kinase activity. In summary the data illustrate specific pathways activated by PDGF-BB and TNF-a in HSC giving new insights into the tightly controlled mechanisms regulating TSP-1 and TGF-beta1 expression in these cells.

Animals↗

PubMed2005

Atypical melting curve resulting from genetic variation in the 3' untranslated region at position 20218 in the prothrombin gene analyzed with the LightCycler factor II (prothrombin) G20210A assay.

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3' Untranslated Regions↗

PubMed2005

Isolation and culture of hepatic stellate cells.

Hepatic stellate cells (HSCs) are routinely prepared by collagenase/pronase digestion of liver using a perfusion system and subsequent fractionation of the heterogeneous cell suspension on continuous density gradients made out of Nycodenz, metrizamide, stractan, or percoll. Because of their lipid content, stellate cells are the least dense fraction of the nonparenchymal cells, and during centrifugation they float effectively away from other hepatic cells resulting in preparations containing almost 80% stellate cells. The degree of purity can be increased by further enrichment of cells by methods like centrifugal elutriation or Scatter-activated cell sorting. We present a detailed protocol from our laboratory to obtain a high number of pure, viable, freshly isolated hepatic stellate cells from rat liver. This two-step protocol (collagenase/pronase digestion and Nycodenz gradient) yields a preparation of approx 4-5 x 107 cells enriched in 74% HSC having a viability of at least 76% as estimated by Trypan blue exclusion test. Further purification by centrifugal elutriation results in virtually pure HSC preparations ( >98%).

Animals↗

PubMed2004

Glucocorticoids decrease the bioavailability of TGF-beta which leads to a reduced TGF-beta signaling in hepatic stellate cells.

Glucocorticoids bound to their receptors transmit information, which regulates numerous physiological and pathophysiological responses, amongst others glucose metabolism, wound healing, inflammation, and stress, either directly as transcription factors by binding DNA elements of target genes or indirectly by protein-protein interactions with other transcription factors. TGF-beta, a key factor in activation of hepatic stellate cells (HSC), induces production of extracellular matrix, this being a prerequisite for the development of liver fibrosis. Glucocorticoids and their receptors may provide a crosstalk with the TGF-beta-Smad signaling pathway by antagonizing TGF-beta effects. We studied the influence of glucocorticoids on the TGF-beta isoform and Smad mRNA expression, TGF-beta secretion, and signaling in activated HSC using gene-specific real-time PCR, ELISA, and transfection techniques. Dexamethasone treatment reduces TGF-beta mRNA transcription in a time-dependent manner. Activated HSC produce TGF-beta and secrete it into the cell culture medium. After dexamethasone treatment, TGF-beta secretion into the medium is reduced dose-dependently but restorable by mifepristone. Further, we found that reduced secretion of endogenous TGF-beta is accompanied by a reduced TGF-beta signal. Additionally, reporter gene analysis after adenoviral infection with a recombinant virus encoding a Smad-binding-element showed that TGF-beta-Smad signaling is significantly down-regulated by dexamethasone in primary HSC and CFSC, a HSC related cell line. Our data suggest that glucocorticoids inhibit TGF-beta expression, prevent TGF-beta from efficient secretion, and finally lead to reduced TGF-beta signaling in primary HSC.

Adrenal Cortex Hormones↗

PubMed2004

Identification of endoglin in rat hepatic stellate cells: new insights into transforming growth factor beta receptor signaling.

Transforming growth factor beta (TGF-beta) signaling is mediated by the cell surface TGF-beta type I (ALK5), type II, and the accessory type III receptors endoglin and betaglycan. Hepatic stellate cells (HSC), the most profibrogenic cell type in the liver, express ALK5, TbetaRII, and betaglycan. To monitor the expression of betaglycan in HSC, we used the commercially available antibody sc-6199 in Western blot analysis. This antibody, raised against a peptide mapping at the carboxyl terminus of the human betaglycan, is claimed to be specific for betaglycan, although it is known that the C-terminal domain is highly conserved in type III receptors. Proteins recognized in HSC by sc-6199 did not match the characteristic migration pattern of betaglycan. Moreover, the determined molecular weight (M(r) 160) and the observed reductant sensitivity after treatment with dithiothreitol resemble those of a closely related type III receptor, endoglin (CD105). Endoglin, a disulfide-linked homodimer, is an accessory component of the TGF-beta receptor complex and mainly expressed on endothelial cells. The presence of endoglin in HSC of rat liver was confirmed by molecular cloning of the endoglin cDNA and immunocytochemistry. The reactivity of sc-6199 with both auxiliary TGF-beta receptors (betaglycan and endoglin) from rats was demonstrated by Western blot and immunocytochemical analysis of cells heterologously expressing these proteins. Furthermore, Northern and Western blotting revealed that both betaglycan and endoglin genes are differentially regulated in HSC and in transdifferentiated myofibroblasts (MFB). By surface labeling and immunoprecipitation experiments, we show that endoglin is found in significant amounts exposed at the plasma membrane of HSC and MFB, which is a pivotal prerequisite for binding of and signaling in response to TGF-beta. In conclusion, we hypothesize that TGF-beta signals in HSC and MFB are tuned by two different interconnected signaling pathways, as it was previously demonstrated for endothelial cells.

Amino Acid Sequence↗

PubMed2004

Antisense strategy against PDGF B-chain proves effective in preventing experimental liver fibrogenesis.

Hepatic stellate cells (HSCs) and transdifferentiated myofibroblasts are the principal producers of excessive extracellular matrix in liver fibrosis and cirrhosis. Activation of HSC is regulated by several cytokines and growth factors, including platelet-derived growth factor B-chain (PDGF-B), a potent mitogen for HSC, and overexpressed during hepatic fibrogenesis. Previous studies showed that MAPK and phosphatidylinositol 3' kinase are key signaling pathways involved in PDGF-induced stimulation of HSC. Based on the involvement of PDGF-B in fibrogenesis, reducing ligand stimulation of proliferative cytokine- or growth factor receptors interfering with receptor signaling therefore presents an interesting strategy for hepatic fibrosis prevention or interruption. We therefore generated an adenoviral vector serotype 5 (Ad5) expressing an antisense mRNA of the PDGF B-chain (Ad5-CMV-asPDGF) for application in an experimentally induced liver fibrogenesis model. The transgene clearly showed the ability to down-regulate endogenous PDGF B-chain and PDGFRbeta mRNA in culture-activated HSC and rat livers. The asPDGF mRNA also attenuates experimental liver fibrogenesis indicated by reduced levels of alpha-SMA and collagen type I expression.

Actins↗

PubMed2004

Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin.

BACKGROUND: Recent studies point to the adipose tissue as a highly active endocrine organ secreting a range of hormones. Leptin, ghrelin, adiponectin, and resistin are considered to take part in the regulation of energy metabolism. APPROACH: This review summarizes recent knowledge on leptin and its receptor and on ghrelin, adiponectin, and resistin, and emphasizes their roles in pathobiochemistry and clinical chemistry. CONTENT: Leptin, adiponectin, and resistin are produced by the adipose tissue. The protein leptin, a satiety hormone, regulates appetite and energy balance of the body. Adiponectin could suppress the development of atherosclerosis and liver fibrosis and might play a role as an antiinflammatory hormone. Increased resistin concentrations might cause insulin resistance and thus could link obesity with type II diabetes. Ghrelin is produced in the stomach. In addition to its role in long-term regulation of energy metabolism, it is involved in the short-term regulation of feeding. These hormones have important roles in energy homeostasis, glucose and lipid metabolism, reproduction, cardiovascular function, and immunity. They directly influence other organ systems, including the brain, liver, and skeletal muscle, and are significantly regulated by nutritional status. This newly discovered secretory function has extended the biological relevance of adipose tissue, which is no longer considered as only an energy storage site. SUMMARY: The functional roles, structures, synthesis, analytical aspects, and clinical significance of leptin, ghrelin, adiponectin, and resistin are summarized.

Adiponectin↗

PubMed2004

Analysis of polymorphic TGFB1 codons 10, 25, and 263 in a German patient group with non-syndromic cleft lip, alveolus, and palate compared with healthy adults.

BACKGROUND: Clefts of the lip, alveolus, and palate (CLPs) rank among the most frequent and significant congenital malformations. Leu10Pro and Arg25Pro polymorphisms in the precursor region and Thr263Ile polymorphism in the prodomain of the transforming growth factor beta1 (TGF-beta1) gene have proved to be crucial to predisposition of several disorders. METHODS: In this study, polymorphism analysis was performed by real-time polymerase chain reaction (LightCycler) and TGF-beta1 levels determined by enzyme-linked immunosorbent assay. RESULTS: Only 2/60 Caucasian non-syndromic patients with CLP (3.3%) carried the Arg25Pro and another 2/60 patients (3.3%) the Thr263Ile genotypes, whereas, in a control group of 60 healthy Caucasian blood donors, these heterozygous genotypes were more frequent 16.7% having Arg25Pro (10/60; p < 0.035) and 10,0% having Thr263Ile (6/60), respectively. TGF-beta1 levels in platelet-poor plasma of heterozygous Arg25Pro individuals were lower than those of homozygous members (Arg25Arg) in the latter group, but this discrepancy narrowly failed to be significant. Although polymorphisms in codon 10 and 25 were associated with each other, no difference was found between patients and controls concerning the Leu10Pro polymorphism. CONCLUSIONS: The genetic differences in codons 25 and 263 suggest that TGF-beta1 could play an important role in occurrence of CLP, however, functional experiments will be required to confirm the mechanisms of disturbed development.

Adolescent↗

PubMed2004

Inhibitory effect of soluble PDGF-beta receptor in culture-activated hepatic stellate cells.

Following liver injury, hepatic stellate cells undergo phenotypic transformation with acquisition of myofibroblast-like features, characterized by increased cell proliferation, motility, contractility, and extracellular matrix production. Activation of hepatic stellate cells is regulated by several cytokines and growth factors, including platelet-derived growth factor B-chain, a potent mitogen for HSC, overexpressed during hepatic fibrogenesis. This pleiotropic mediator exerts cellular effects by binding to specific receptors, inducing receptor dimerization and tyrosine-autophosphorylation. Activated receptor phosphotyrosines recruit signal transduction molecules, initiating various signaling pathways. We produced a soluble PDGFbeta-receptor (sPDGFRbeta) consisting of an extracellular domain connected to the IgG-Fc part of human immunoglobulin heavy chain. This soluble, chimeric receptor inhibits PDGF signaling and PDGF-induced proliferation in culture-activated hepatic stellate cells. Furthermore, sPDGFR decreased collagen type I (alphaI) mRNA expression and inhibits autocrine-looping in PDGF-BB mRNA production. In summary, sPDGFRbeta clearly shows effective inhibitory properties in early HSC activation, suggesting potential therapeutic impact for anti-PDGF intervention in liver fibrogenesis.

Amino Acid Sequence↗

PubMed2004

Induction of cell death in activated hepatic stellate cells by targeted gene expression of the thymidine kinase/ganciclovir system.

Liver fibrosis is the result from a relative imbalance between synthesis and degradation of matrix proteins. Following liver injury of any etiology, hepatic stellate cells undergo a response known as activation, which is the transition of quiescent cells into proliferative, fibrogenic, and contractile myofibroblasts. Upon this cellular transdifferentiation the effector cell becomes the major source of fibrillar and non-fibrillar matrix proteins resulting in excessive scar formation and cirrhosis, the end stage of fibrosis. Concomitant with progressive liver fibrosis, the tissue inhibitor of metalloproteinases-1 (TIMP-1) is strongly activated in hepatic stellate cells. We have developed a recombinant replication-defective adenovirus in which the TIMP-1 promoter is coupled to the herpes simplex virus thymidine kinase gene rendering activated hepatic stellate cells susceptible to ganciclovir. This novel targeted suicide gene approach was validated in a culture model considered to reflect an accelerated time course of the cellular and molecular events that occur during liver fibrosis. We demonstrate that transfer of the suicide gene to culture-activated hepatic stellate cells results in a strong expression of the respective transgene as assessed by Northern blot and Western blot analyses. The enzyme catalyzed the proper conversion of its prodrug subsequently initiating programmed cell death as estimated by caspase-3 assay and Annexin V-Fluos staining. Altogether, these results indicate that induction of programmed cell death is a promising approach to eliminate fibrogenic HSC.

Animals↗

PubMed2004

Corticosteroids stimulate selectively transforming growth factor (TGF)-beta receptor type III expression in transdifferentiating hepatic stellate cells.

BACKGROUND/AIMS: Transforming growth factor (TGF)-beta receptors mediate TGF-beta signaling in activated hepatic stellate cells (HSC). This leads to pleiotropic cellular effects, e.g. to the production of extracellular matrix which is a hallmark for the development of liver fibrosis. Glucocorticoids and their receptors interact with the TGF-beta signaling pathway on the transcriptional and translational level. METHODS: To characterize TGF-beta receptor expression during HSC transdifferentiation and to study the influence of corticosteroids on receptor transcription in several liver cells, we established a real-time polymerase chain reaction procedure for mRNA quantification with gene-specific standards. RESULTS: All three TGF-beta receptor mRNAs are present in HSC and myofibroblasts. Whereas TGF beta receptor type I (T beta RI) shows a comparable mRNA expression during HSC transdifferentiation, T beta RII and T beta RIII mRNA concentration decreases in the course of time. In comparison with activated HSC T beta RIII mRNA is very low expressed in freshly isolated Kupffer cells and hepatocytes. Eight hours after corticosteroid treatment T beta RIII mRNA increased significantly in a time-and dose-dependent manner while the mRNA expression of T beta RI and T beta RII is not altered. The degree of induction of T beta RIII mRNA levels is also dependent upon the nature of the stimulating hormone: dexamethasone, hydrocortisone and aldosterone show different effects. CONCLUSIONS: The increase of T beta RIII by corticosteroids indicates that these hormones are important regulators of this receptor and thereby they can modulate TGF-beta signaling.

Activin Receptors, Type I↗

PubMed2004

Dominant-negative soluble PDGF-beta receptor inhibits hepatic stellate cell activation and attenuates liver fibrosis.

Hepatic fibrogenesis is a consequence of hepatic stellate cells that become activated and transdifferentiate into a myofibroblastic phenotype with the ability to proliferate and synthesize large quantities of extracellular matrix components. In this process, platelet-derived growth factor (PDGF) is the most potent stimulus for hepatic stellate cell proliferation and migration, and is overexpressed during active hepatic fibrogenesis. This cytokine binds to the PDGF receptor type beta, activates Ras and sequentially propagates the stimulatory signal sequentially via phosphorylation of Raf-1, MEK and the extracellular-signal regulated kinases ERK1/ERK2. Hepatic injury is associated with both increased autocrine PDGF signaling and upregulation of PDGF receptor. In this study, we report that a dominant-negative soluble PDGF-beta receptor consisting of a chimeric IgG containing the extracellular portion of the PDGF receptor type beta blocks HSC activation and attenuates fibrogenesis induced by ligation of the common bile duct in rats. In culture-activated hepatic stellate cells, the soluble receptor blocks phosphorylation of endogenous PDGF receptor, phosphorylation of the ERK1/EKR2 signal and reduces proliferative activities of HSC. In vivo, both the delivery of the purified soluble PDGF antagonist and the administration of adenoviruses expressing the artificial transgene were able to reduce significantly the expression of collagen and alpha-smooth muscle actin. Our results demonstrate that PDGF plays a critical role in the progression and initiation of experimental liver fibrogenesis, and suggest that early anti-PDGF intervention should have a therapeutical impact on the treatment of liver fibrogenesis.

Adenoviridae↗

PubMed2004

Hyperglycemia at admission to the intensive care unit is associated with elevated serum concentrations of interleukin-6 and reduced ex vivo secretion of tumor necrosis factor-alpha.

OBJECTIVES: The aim of the study was to investigate the association between admission blood glucose concentrations and immune function variables and its correlation to mortality rate in patients of a medical intensive care unit. DESIGN: Prospective, observational study. SETTING: Medical intensive care unit of a university hospital. PATIENTS: Patients were 189 consecutive critically ill patients in the medical intensive care unit. INTERVENTIONS: At admission to the intensive care unit, serum concentrations of interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor-alpha were measured with immunometric assays. Additionally, ex vivo secretion of tumor necrosis factor-alpha after stimulation with lipopolysaccharide in a whole blood assay and cytometric human leukocyte antigen-DR expression on monocytes were determined in all study subjects. Simplified Acute Physiology Score II and Therapeutic Intervention Scoring System-28 were calculated for the first day in the intensive care unit. MEASUREMENTS AND MAIN RESULTS: The relationships between blood glucose concentrations and immunologic variables were analyzed using univariate and multivariate statistical methods. Overall, 75 patients (39.7%) presented with hyperglycemia. An elevated blood glucose concentration at admission was related to an increased risk of mortality in the intensive care unit (odds ratio, 2.6; p = .009). At univariate and multivariate analysis, hyperglycemia was associated with increased serum concentrations of interleukin-6 (p < .05), a reduced ex vivo production of tumor necrosis factor-alpha (p < .01), and a history of diabetes mellitus (p < .05), whereas other clinical (including Simplified Acute Physiology Score II and Therapeutic Intervention Scoring System-28) and immunologic variables were not statistically related to blood glucose. CONCLUSIONS: Our main findings show that admission hyperglycemia is statistically related to distinct changes of humoral and cellular immune functions. Furthermore, elevated glucose concentrations at admission are associated with increased intensive care unit mortality rate in a medical intensive care unit. Although these data do not explain cause and effect, our results provide a strong rationale for studying the immunologic effects of strict glycemic control in the intensive care unit during the course of critical illness.

APACHE↗