Effects of Recombinant Human Growth Hormone in Patients With Severe Sepsis

Voerman, H. J.; Schijndel, R J van; Groeneveld, A. B. J.; Boer, H. de; Nauta, Jos P.; Veen, E. A. Van Der; Thijs, L. G.

doi:10.1097/00000658-199212000-00006

Cited by 147 publications

(40 citation statements)

References 35 publications

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“…Indeed, when critically ill patients were treated with human growth hormone, the mortality rate was increased, suggesting that prevention of muscle breakdown in critical illness may actually be harmful (34). Results in that study, however, are controversial, and in several other reports (21,25,32,38), treatment of critically ill patients with human growth hormone did not result in adverse effects but improved nitrogen balance and wound healing. As suggested by others (30,32) and by Takala et al (34), it is possible that the increased mortality in human growth hormone-treated patients in the study by Takala et al (34) reflected suboptimal control of blood sugar levels rather than prevention of muscle proteolysis.…”

Section: Discussionmentioning

confidence: 82%

Treatment of rats with calpain inhibitors prevents sepsis-induced muscle proteolysis independent of atrogin-1/MAFbx and MuRF1 expression

Fareed¹,

Evenson²,

Wei³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

114

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-Muscle wasting in sepsis is a significant clinical problem because it results in muscle weakness and fatigue that may delay ambulation and increase the risk for thromboembolic and pulmonary complications. Treatments aimed at preventing or reducing muscle wasting in sepsis, therefore, may have important clinical implications. Recent studies suggest that sepsis-induced muscle proteolysis may be initiated by calpain-dependent release of myofilaments from the sarcomere, followed by ubiquitination and degradation of the myofilaments by the 26S proteasome. In the present experiments, treatment of rats with one of the calpain inhibitors calpeptin or BN82270 inhibited protein breakdown in muscles from rats made septic by cecal ligation and puncture. The inhibition of protein breakdown was not accompanied by reduced expression of the ubiquitin ligases atrogin-1/MAFbx and MuRF1, suggesting that the ubiquitin-proteasome system is regulated independent of the calpain system in septic muscle. When incubated muscles were treated in vitro with calpain inhibitor, protein breakdown rates and calpain activity were reduced, consistent with a direct effect in skeletal muscle. Additional experiments suggested that the effects of BN82270 on muscle protein breakdown may, in part, reflect inhibited cathepsin L activity, in addition to inhibited calpain activity. When cultured myoblasts were transfected with a plasmid expressing the endogenous calpain inhibitor calpastatin, the increased protein breakdown rates in dexamethasone-treated myoblasts were reduced, supporting a role of calpain activity in atrophying muscle. The present results suggest that treatment with calpain inhibitors may prevent sepsis-induced muscle wasting. ubiquitin ligases; calpains MUSCLE WASTING DURING SEPSIS is mainly caused by an increase in protein breakdown, in particular, breakdown of the myofibrillar proteins actin and myosin (17,36). Previous studies from our and other laboratories suggest that muscle proteolysis in sepsis and a number of other catabolic conditions, such as burn injury, cancer, and uremia, reflects ubiquitin-proteasomedependent proteolysis (11,13,17,36,44). Proteins degraded by this mechanism are first conjugated to multiple molecules of ubiquitin followed by degradation by the 26S proteasome (22). Ubiquitination of the protein substrates is regulated by multiple enzymes, including the ubiquitin-activating enzyme E1, ubiquitin-conjugating enzymes (E2s), and ubiquitin ligases (E3s). Among these enzymes, the E3s are particularly important because they account for substrate specificity in the system. In recent studies, the expression of two newly discovered musclespecific ubiquitin ligases, atrogin-1/MAFbx and MuRF1, was substantially increased in skeletal muscle during various muscle-wasting conditions, including sepsis (5, 15, 45), and increased mRNA levels for atrogin-1/MAFbx and MuRF1 have been suggested to be reliable molecular markers for muscle atrophy (28).Although ubiquitin-proteasome-dependent protein degradation plays an important ...

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Section: Discussionmentioning

confidence: 82%

Treatment of rats with calpain inhibitors prevents sepsis-induced muscle proteolysis independent of atrogin-1/MAFbx and MuRF1 expression

Fareed¹,

Evenson²,

Wei³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

114

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“…However, an early study by Soroff et al [8] in 1967 demonstrated that GH was ineffective during the early ebb phase, but improved nitrogen balance in the anabolic phase of thermal injury. Later, both GH and insulin-like growth factor-1 (IGF-1) have preliminarily been investigated in the severe catabolism seen in septicemia [3,[9][10][11]. The results of these studies indicate that patients who recovered from the initial acute catabolic responses seem to have positive effects of GH.…”

Section: Introductionmentioning

confidence: 99%

Treatment with Growth Hormone and Insulin-Like Growth Factor-1 in Septicemia: Effects on Carbohydrate Metabolism

Balteskard¹,

Unneberg²,

Mjaaland³

et al. 1998

Eur Surg Res

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Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) may be beneficial against the protein catabolism seen in injury and septicemia. Further understanding of their effects on carbohydrate metabolism is needed. In a septic porcine model receiving total parenteral nutrition, pretreatment with GH or IGF-1 (or no treatment in controls) was followed by an infusion of live Escherichia coli bacteria. Endogenous glucose production, carbohydrate oxidation, glucose and lactate fluxes over the liver, gastrointestinal organs, kidney, and hindleg were determined. Endogenous glucose production increased during septicemia in the GH group. The metabolic acidosis induced by septicemia was augmented by GH, but attenuated by IGF-1. The alanine and lactate levels were significantly higher in the GH- than in the IGF-1-treated animals during septicemia. IGF-1 pretreatment appeared to induce favorable effects while GH pretreatment might produce unfavorable effects on carbohydrate metabolism in septic piglets.

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“…Sepsis is also associated with a wide range of hormonal changes that contribute to the catabolic state; among these there is an alteration of the somatotropic axis (47). A decrease in serum concentrations of IGF-I in septic patients and in different inflammatory diseases has also been observed (12,28).…”

mentioning

confidence: 99%

NO plays a role in LPS-induced decreases in circulating IGF-I and IGFBP-3 and their gene expression in the liver

Priego

Cáceres²,

Martín³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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Priego, Teresa, Inmaculada Ibáñez de Cáceres, Ana Isabel Martín, M. Á ngeles Villanú a, and Asunción López-Calderón. NO plays a role in LPS-induced decreases in circulating IGF-I and IGFBP-3 and their gene expression in the liver. Am J Physiol Endocrinol Metab 286: E50-E56, 2004. First published September 16, 2003 10.1152/ajpendo.00149.2003In this study, we administered aminoguanidine, a relatively selective inducible nitric oxide synthase (iNOS) inhibitor, to study the role of nitric oxide (NO) in LPSinduced decrease in IGF-I and IGFBP-3. Adult male Wistar rats were injected intraperitoneally with LPS (100 g/kg), aminoguanidine (100 mg/kg), LPS plus aminoguanidine, or saline. Rats were injected at 1730 and 0830 the next day and killed 4 h after the last injection. LPS administration induced an increase in serum concentrations of nitrite/ nitrate (P Ͻ 0.01) and a decrease in serum concentrations of growth hormone (GH; P Ͻ 0.05) and IGF-I (P Ͻ 0.01) as well as in liver IGF-I mRNA levels (P Ͻ 0.05). The LPS-induced decrease in serum concentrations of IGF-I and liver IGF-I gene expression seems to be secondary to iNOS activation, since aminoguanidine administration prevented the effect of LPS on circulating IGF-I and its gene expression in the liver. In contrast, LPS-induced decrease in serum GH was not prevented by aminoguanidine administration. LPS injection decreased IGFBP-3 circulating levels (P Ͻ 0.05) and its hepatic gene expression (P Ͻ 0.01), but endotoxin did not modify the serum IGFBP-3 proteolysis rate. Aminoguanidine administration blocked the inhibitory effect of LPS on both IGFBP-3 serum levels and its hepatic mRNA levels. When aminoguanidine was administered alone, IGFBP-3 serum levels were increased (P Ͻ 0.05), whereas its hepatic mRNA levels were decreased. This contrast can be explained by the decrease (P Ͻ 0.05) in serum proteolysis of this binding protein caused by aminoguanidine. These data suggest that iNOS plays an important role in LPS-induced decrease in circulating IGF-I and IGFBP-3 by reducing IGF-I and IGFBP-3 gene expression in the liver. nitric oxide; inducible nitric oxide synthase; lipopolysaccharide; growth hormone; insulin-like growth factor I; insulin-like growth factor-binding protein-3; proteolysis; aminoguanidine SEPSIS INDUCES PROTEOLYSIS and negative nitrogen balance, which leads to lean body mass loss and cachexia. Sepsis is also associated with a wide range of hormonal changes that contribute to the catabolic state; among these there is an alteration of the somatotropic axis (47). A decrease in serum concentrations of IGF-I in septic patients and in different inflammatory diseases has also been observed (12,28).Lipopolysaccharide (LPS), or endotoxin, triggers the initiation of host responses to sepsis by gram-negative bacterial infection. Endotoxin administration in rats increases plasma concentrations of corticosterone, whereas it decreases circulating growth hormone (GH) and IGF-I (20, 27). The decrease in circulating IGF-I is secondary to a decrease in IGF-I gene expres...

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Effects of Recombinant Human Growth Hormone in Patients With Severe Sepsis

Cited by 147 publications

References 35 publications

Treatment of rats with calpain inhibitors prevents sepsis-induced muscle proteolysis independent of atrogin-1/MAFbx and MuRF1 expression

Treatment of rats with calpain inhibitors prevents sepsis-induced muscle proteolysis independent of atrogin-1/MAFbx and MuRF1 expression

Treatment with Growth Hormone and Insulin-Like Growth Factor-1 in Septicemia: Effects on Carbohydrate Metabolism

NO plays a role in LPS-induced decreases in circulating IGF-I and IGFBP-3 and their gene expression in the liver

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