|
1
|
Abstract
Hypermetabolism is a hallmark of larger burn injuries. The hypermetabolic response is characterized by marked and sustained increases in catecholamines, glucocorticoids, and glucagon. There is an increasing body of literature for nutrition and metabolic treatment and supplementation to counter the hypermetabolic and catabolic response secondary to burn injury. Early and adequate nutrition is key in addition to adjunctive therapies, such as oxandrolone, insulin, metformin, and propranolol. The duration of administration of anabolic agents should be at minimum for the duration of hospitalization, and possibly up to 2 to 3 years postburn.
Collapse
Affiliation(s)
- Shahriar Shahrokhi
- Burn Program at Hamilton Health Sciences, Hamilton, Ontario, Canada; Department of Surgery, McMaster University, Hamilton, Ontario, Canada
| | - Marc G Jeschke
- Burn Program at Hamilton Health Sciences, Hamilton, Ontario, Canada; Department of Surgery, McMaster University, Hamilton, Ontario, Canada; TaAri Institute, Hamilton Health Sciences Research Institute, Hamilton, Ontario, Canada; David Braley Research Institute, C5-104, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.
| |
Collapse
|
|
2
|
Muacevic A, Adler JR, Torres R, Maita K, Garcia J, Serrano L, Ho O, Forte AJ. Modulation of Burn Hypermetabolism in Preclinical Models. Cureus 2023; 15:e33518. [PMID: 36779088 PMCID: PMC9904913 DOI: 10.7759/cureus.33518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/08/2023] [Indexed: 01/11/2023] Open
Abstract
Severe burns elicit a state of physiological stress and increased metabolism to help the body compensate for the changes associated with the traumatic injury. However, this hypermetabolic state is associated with increased insulin resistance, cardiovascular dysfunction, skeletal muscle catabolism, impaired wound healing, and delayed recovery. Several interventions were attempted to modulate burn hypermetabolism, including nutritional support, early excision and grafting, and growth hormone application. However, burn hypermetabolism still imposes significant morbidity and mortality in burn patients. Due to the limitations of in vitro models, animal models are indispensable in burn research. Animal models provide researchers with invaluable tools to test the safety and efficacy of novel treatments or advance our knowledge of previously utilized agents. Several animal studies evaluated novel therapies to modulate burn hypermetabolism in the last few years, including recombinant human growth hormone, erythropoietin, acipimox, apelin, anti-interleukin-6 monoclonal antibody, and ghrelin therapies. Results from these studies are promising and may be effectively translated into human studies. In addition, other studies revisited drugs previously used in clinical practice, such as insulin and metformin, to further investigate their underlying mechanisms as modulators of burn hypermetabolism. This review aims to update burn experts with the novel therapies under investigation in burn hypermetabolism with a focus on applicability and translation. Furthermore, we aim to guide researchers in selecting the correct animal model for their experiments by providing a summary of the methodology and the rationale of the latest studies.
Collapse
|
|
3
|
Abstract
Severe burn injury is followed by a profound hypermetabolic response that persists up to 2 years after injury. It is mediated by up to 50-fold elevations in plasma catecholamines, cortisol, and glucagon that lead to whole-body catabolism, elevated resting energy expenditures, and multiorgan dysfunction. Modulation of the response by early excision and grafting of burn wounds, thermoregulation, control of infection, early and continuous enteral nutrition, and pharmacologic treatments aimed at mitigating physiologic derangements have markedly decreased morbidity.
Collapse
Affiliation(s)
- Felicia N Williams
- Department of Surgery, North Carolina Jaycee Burn Center, University of North Carolina, Chapel Hill, 3007D Burnett Womack Building, CB 7206, Chapel Hill, NC 27599-7206, USA
| | - David N Herndon
- Department of Surgery, Shriners Hospital of Children, University of Texas Medical Branch, 815 Market Street, Galveston, TX 77550, USA.
| |
Collapse
|
|
4
|
Abstract
Hypermetabolism is the ubiquitous response to a severe burn injury, which was first described in the nineteenth century. Despite identification of important components of this complex response, hypermetabolism is still not well understood in its entirety. This article describes this incredibly fascinating response and the understanding we have gained over the past 100 years. Additionally, this article describes novel insights and delineates treatment options to modulate postburn hypermetabolism with the goal to improve outcomes of burn patients.
Collapse
|
|
5
|
Lee OJ, Ju HW, Khang G, Sun PP, Rivera J, Cho JH, Park SJ, Eden JG, Park CH. An experimental burn wound-healing study of non-thermal atmospheric pressure microplasma jet arrays. J Tissue Eng Regen Med 2015; 10:348-57. [PMID: 26227832 DOI: 10.1002/term.2074] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Revised: 05/10/2015] [Accepted: 06/12/2015] [Indexed: 11/09/2022]
Abstract
In contrast with a thermal plasma surgical instrument based on coagulative and ablative properties, low-temperature (non-thermal) non-equilibrium plasmas are known for novel medicinal effects on exposed tissue while minimizing undesirable tissue damage. In this study we demonstrated that arrays of non-thermal microplasma jet devices fabricated from a transparent polymer can efficiently inactivate fungi (Candida albicans) as well as bacteria (Escherichia coli), both in vitro and in vivo, and that this leads to a significant wound-healing effect. Microplasma jet arrays offer several advantages over conventional single-jet devices, including superior packing density, inherent scalability for larger treatment areas, unprecedented material flexibility in a plasma jet device, and the selective generation of medically relevant reactive species at higher plasma densities. The therapeutic effects of our multi-jet device were verified on second-degree burns in animal rat models. Reduction of the wound area and the histology of the wound after treatment have been investigated, and expression of interleukin (IL)-1α, -6 and -10 was verified to evaluate the healing effects. The consistent effectiveness of non-thermal plasma treatment has been observed especially in decreasing wound size and promoting re-epithelialization through collagen arrangement and the regulation of expression of inflammatory genes.
Collapse
Affiliation(s)
- Ok Joo Lee
- Nano-Bio Regenerative Medical Institute, Hallym University, Chuncheon, Gangwon, Republic of Korea
| | - Hyung Woo Ju
- Nano-Bio Regenerative Medical Institute, Hallym University, Chuncheon, Gangwon, Republic of Korea
| | - Gilson Khang
- Department of BIN Fusion Technology, Department of Polymer Nanoscience and Technology and Polymer BIN Research Centre, Chonbuk National University, Republic of Korea
| | - Peter P Sun
- Laboratory for Optical Physics and Engineering, Department of Electrical and Computer Engineering, University of Illinois, Urbana, IL, USA
| | - Jose Rivera
- Laboratory for Optical Physics and Engineering, Department of Electrical and Computer Engineering, University of Illinois, Urbana, IL, USA
| | - Jin Hoon Cho
- Laboratory for Optical Physics and Engineering, Department of Electrical and Computer Engineering, University of Illinois, Urbana, IL, USA
| | - Sung-Jin Park
- Laboratory for Optical Physics and Engineering, Department of Electrical and Computer Engineering, University of Illinois, Urbana, IL, USA
| | - J Gary Eden
- Laboratory for Optical Physics and Engineering, Department of Electrical and Computer Engineering, University of Illinois, Urbana, IL, USA
| | - Chan Hum Park
- Nano-Bio Regenerative Medical Institute, Hallym University, Chuncheon, Gangwon, Republic of Korea.,Department of Otorhinolaryngology-Head and Neck Surgery, Chuncheon Sacred Heart Hospital, School of Medicine, Hallym University, Chuncheon, Gangwon, Republic of Korea
| |
Collapse
|
|
6
|
Abstract
BACKGROUND Recombinant human growth hormone (rhGH) increases protein synthesis, therefore it is used in burns with a total body surface area (TBSA) greater than 40%, where there is frequently an increase in protein breakdown and a decrease in protein synthesis. This change in protein metabolism correlates with poor wound healing of the burn and donor sites. OBJECTIVES To determine the effects of rhGH on the healing rate of burn wounds and donor sites in people with burns. SEARCH METHODS For this first update we searched the Cochrane Wounds Group Specialised Register (searched 04 September 2014); The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 8); Database of Abstracts of Reviews of Effects (DARE) (The Cochrane Library 2014, Issue 3); Ovid MEDLINE (1950 to September Week 4 2014); Ovid MEDLINE (In-Process & Other Non-Indexed Citations September 8, 2014); Ovid EMBASE (1980 to 2014 Week 35); and EBSCO CINAHL (1982 to 8 September 2014). SELECTION CRITERIA Randomised controlled trials (RCTs) comparing rhGH with any comparator intervention, e.g. oxandrolone or placebo, in adults or children with burns. DATA COLLECTION AND ANALYSIS Two review authors independently selected studies, assessed trial quality and extracted data. The primary outcomes were the healing of the burn wound and donor sites and the occurrence of wound infections. The secondary outcomes were mortality rate, length of hospital stay, scar assessment, and adverse events: hyperglycaemia and septicaemia. MAIN RESULTS We included 13 RCTs (701 people). Six of the RCTs included only children aged 1 to 18 years and seven involved only adults (from 18 to 65 years of age). The mean TBSA of the included participants was greater than 49%. Twelve studies compared rhGH with placebo and one study compared rhGH with oxandrolone. Two trials found that compared with placebo, burn wounds in adults treated with rhGH healed more quickly (by 9.07 days; 95% confidence interval (CI) 4.39 to 13.76, I² = 0%). The donor site healing time was significantly shorter in rhGH-treated adults compared with placebo-treated participants (by 3.15 days; 95% CI 1.54 to 4.75, I² = 0%). Two studies in children with the outcome of donor site healing time could be pooled and the donor site healing time was shorter in the rhGH-treated children (by 1.70 days; 95% CI 0.87 to 2.53, I² = 0%). No studies reporting the outcome of wound infection were found. The incidence of hyperglycaemia was higher in adults during rhGH treatment compared with placebo (risk ratio (RR) 2.43; 95% CI 1.54 to 3.85), but not in children. Pooling the studies of adults and children yielded a significantly higher incidence of hyperglycaemia in the rhGH-treated participants (RR 2.65; 95% CI 1.68 to 4.16). AUTHORS' CONCLUSIONS There is some evidence that using rhGH in people with large burns (more than 40% of the total body surface area) could result in more rapid healing of the burn wound and donor sites in adults and children, and in reduced length of hospital stay, without increased mortality or scarring, but with an increased risk of hyperglycaemia. This evidence is based on studies with small sample sizes and risk of bias and requires confirmation in higher quality, adequately powered trials.
Collapse
Affiliation(s)
- Roelf S Breederveld
- Red Cross HospitalSurgery and Burn CentreVondellaan 13BeverwijkNHNetherlands1942 LE
| | - Wim E Tuinebreijer
- Red Cross HospitalSurgery and Burn CentreVondellaan 13BeverwijkNHNetherlands1942 LE
| | | |
Collapse
|
|
7
|
Abstract
Outcomes of patients with burns have improved substantially over the past two decades. Findings from a 2012 study in The Lancet showed that a burn size of more than 60% total body surface area burned (an increase from 40% a decade ago) is associated with risks and mortality. Similar data have been obtained in adults and elderly people who have been severely burned. We discuss recent and future developments in burn care to improve outcomes of children.
Collapse
Affiliation(s)
- Marc G Jeschke
- Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto, Canada; Department of Surgery, Division of Plastic Surgery, Department of Immunology, University of Toronto, Toronto, Canada; Sunnybrook Research Institute, Toronto, Canada.
| | - David N Herndon
- Shriners Hospitals for Children and Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA
| |
Collapse
|
|
8
|
Abstract
BACKGROUND Recombinant human growth hormone (rhGH) increases protein synthesis, therefore it is used in burns with a total body surface area (TBSA) greater than 40%, where there is frequently an increase in protein breakdown and a decrease in protein synthesis. This change in protein metabolism correlates with poor wound healing of the burn and donor sites. OBJECTIVES To determine the effects of rhGH on the healing rate of burn wounds and donor sites in people with burns. SEARCH METHODS We searched the Cochrane Wounds Group Specialised Register (searched 28 June 2012); The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 6); Database of Abstracts of Reviews of Effects (DARE) (The Cochrane Library 2011, Issue 3); Ovid MEDLINE (1950 to June Week 3 2012); Ovid MEDLINE (In-Process & Other Non-Indexed Citations June 27, 2012); Ovid EMBASE (1980 to 2012 Week 25); and EBSCO CINAHL (1982 to 21 June 2012). SELECTION CRITERIA Randomised controlled trials (RCTs) comparing rhGH with any comparator intervention, e.g. oxandrolone or placebo, in adults or children with burns. DATA COLLECTION AND ANALYSIS Two review authors independently selected studies, assessed trial quality and extracted data. The primary outcomes were the healing of the burn wound and donor sites and the occurrence of wound infections. The secondary outcomes were mortality rate, length of hospital stay, scar assessment, and adverse events: hyperglycaemia and septicaemia. MAIN RESULTS We included 13 RCTs (701 people). Six of the RCTs included only children aged 1 to 18 years and seven involved only adults (from 18 to 65 years of age). The mean TBSA of the included participants was greater than 49%. Twelve studies compared rhGH with placebo and one study compared rhGH with oxandrolone. Two trials found that compared with placebo, burn wounds in adults treated with rhGH healed more quickly (by 9.07 days; 95% confidence interval (CI) 4.39 to 13.76, I² = 0%). The donor site healing time was significantly shorter in rhGH-treated adults compared with placebo-treated participants (by 3.15 days; 95% CI 1.54 to 4.75, I² = 0%). Two studies in children with the outcome of donor site healing time could be pooled and the donor site healing time was shorter in the rhGH-treated children (by 1.70 days; 95% CI 0.87 to 2.53, I² = 0%). No studies reporting the outcome of wound infection were found. The incidence of hyperglycaemia was higher in adults during rhGH treatment compared with placebo (risk ratio (RR) 2.43; 95% CI 1.54 to 3.85), but not in children. Pooling the studies of adults and children yielded a significantly higher incidence of hyperglycaemia in the rhGH-treated participants (RR 2.65; 95% CI 1.68 to 4.16). AUTHORS' CONCLUSIONS There is some evidence that using rhGH in people with large burns (more than 40% of the total body surface area) could result in more rapid healing of the burn wound and donor sites in adults and children, and in reduced length of hospital stay, without increased mortality or scarring, but with an increased risk of hyperglycaemia. This evidence is based on studies with small sample sizes and risk of bias and requires confirmation in higher quality, adequately powered trials.
Collapse
|
|
9
|
Wang T, Hai J, Chen X, Peng H, Zhang H, Li L, Zhang Q. Inhibition of GHRH aggravated acetaminophen-induced acute mice liver injury through GH/IGF-I axis. Endocr J 2012; 59:579-87. [PMID: 22572547 DOI: 10.1507/endocrj.ej11-0356] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The aim of the current study is to investigate the effects of growth hormone releasing hormone (GHRH) antagonist on acetaminophen (APAP)-induced acute liver injury in mice. Healthy C57/B6L mice were orally treated with 200 mg/kg APAP with or without a 30-min pre-treatment with 300 µg/kg GHRH antagonist MZ-5-156. After 12 hours, serum, plasma, and liver samples from each mouse were collected for analyses. Our results showed that twelve-hour treatment with APAP caused obvious liver injury, elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, increased oxidative stress, reduced expressions of antioxidant enzymes, accumulated expression of pro-inflammatory cytokines, and increased circulating levels of growth hormone (GH) and insulin-like growth factor-I (IGF-I). Pre-treatment with MZ-5-156 aggravated liver injury, further increased serum ALT and AST levels, exacerbated oxidative stress and inflammation induced by APAP. Treatment of MZ-5-156 also blocked the phosphorylation form and total form of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5). Treatment of GHRH super-agonist JI-38 immediately after MZ-5-156 treatment partly reversed the liver injury caused by APAP and MZ-5-156. In conclusion, GHRH plays essential protective role in APAP-induced acute liver injury in vivo. The protective properties of GHRH are partially through GH/IGF-I axis and JAK/STAT pathway.
Collapse
Affiliation(s)
- Tao Wang
- First affiliated hospital, Xinxiang Medical University, Henan, China
| | | | | | | | | | | | | |
Collapse
|
|
10
|
Abstract
The Growth Hormone and Insulin-like Growth Factor-1 (IGF-1) axis plays a pivotal role in critical illness, with a derangement leading to profound changes in metabolism. Protein wasting with skeletal muscle loss, delayed wound healing, and impaired recovery of organ systems are some of the most feared consequences. The use of human recombinant Growth Hormone (rhGH) and Insulin-like Growth Factor-1 (IGF-1) - alone and in combination - has been studied extensively in preclinical and clinical trials. This article reviews the current knowlegde and clinical practice of the use of rhGh and IGF-1 in critically ill patients, with a special focus on the trauma and burns patient population.
Collapse
Affiliation(s)
- Itoro E Elijah
- Department of Surgery, University of Texas Medical Branch and Shriners Hospitals for Children, 815 Market Street, Galveston, TX 77550, United States
| | | | | | | |
Collapse
|
|
11
|
Williams FN, Branski LK, Jeschke MG, Herndon DN. What, how, and how much should patients with burns be fed? Surg Clin North Am 2011; 91:609-29. [PMID: 21621699 DOI: 10.1016/j.suc.2011.03.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The hypermetabolic response to severe burn injury is characterized by hyperdynamic circulation and profound metabolic, physiologic, catabolic, and immune system derangements. Failure to satisfy overwhelming energy and protein requirements after, and during, severe burn injury results in multiorgan dysfunction, increased susceptibility to infection, and death. Attenuation of the hypermetabolic response by various pharmacologic modalities is emerging as an essential component of the management of patients with severe burn injury. This review focuses on the more recent advances in therapeutic strategies to attenuate the hypermetabolic response and its postburn-associated insulin resistance.
Collapse
Affiliation(s)
- Felicia N Williams
- Department of Surgery, Shriners Hospital for Children and University of Texas Medical Branch, 815 Market Street, Galveston, TX 77550, USA
| | | | | | | |
Collapse
|
|
12
|
Williams FN, Herndon DN, Jeschke MG. The hypermetabolic response to burn injury and interventions to modify this response. Clin Plast Surg 2009; 36:583-96. [PMID: 19793553 PMCID: PMC3776603 DOI: 10.1016/j.cps.2009.05.001] [Citation(s) in RCA: 154] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Severe burn injury is followed by a profound hypermetabolic response that persists up to 24 months after injury. It is mediated by up to 50-fold elevations in plasma catecholamines, cortisol, and inflammatory cells that lead to whole-body catabolism, elevated resting energy expenditures, and multiorgan dysfunction. All of these metabolic and physiologic derangements prevent full rehabilitation and acclimatization of burn survivors back into society. Modulation of the response by early excision and grafting of burn wounds, thermoregulation, early and continuous enteral feeding with high-protein high-carbohydrate feedings, and pharmacologic treatments have markedly decreased morbidity.
Collapse
Affiliation(s)
- Felicia N Williams
- NIH Research Fellow, Department of Surgery, The University of Texas Medical Branch, Galveston, Texas
| | - David N Herndon
- Professor, Department of Surgery, The University of Texas Medical Branch, Galveston, Texas
- Shriners Hospitals for Children, Galveston, Texas
| | - Marc G Jeschke
- Associate Professor, Department of Surgery, The University of Texas Medical Branch, Galveston, Texas
- Shriners Hospitals for Children, Galveston, Texas
| |
Collapse
|
|
13
|
Berczi I, Quintanar-Stephano A, Kovacs K. Neuroimmune regulation in immunocompetence, acute illness, and healing. Ann N Y Acad Sci 2009; 1153:220-39. [PMID: 19236345 DOI: 10.1111/j.1749-6632.2008.03975.x] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Adaptive immunocompetence is maintained by growth hormone (GH), prolactin (PRL), and vasopressin (VP). Innate or natural immunocompetence depends on cytokines, hormones (especially of the hypothalamus-pituitary-adrenal axis), and catecholamines. The acute phase response (APR, or acute febrile illness) is an emergency defense reaction whereby the adaptive, T cell-dependent, immune reactions are suppressed and the innate immune function is dramatically amplified. Infection and various forms of injury induce APR. Cytokines [interleukin (IL)-1beta, tumor necrosis factor-alpha, and IL-6] stimulate corticotropin-releasing hormone (CRH) and VP secretion and cause a "sympathetic outflow." Colony-stimulating factors activate leukocytes. CRH is a powerful activator of the pituitary adrenocortical axis and elevates glucocorticoid (GC) levels. Cytokines, GCs, and catecholamines play fundamental roles in the amplification of natural immune defense mechanisms. VP supports the APR at this stage. However, VP remains active and is elevated for a longer period than is CRH. VP, but not CRH, is elevated during chronic inflammatory diseases. VP controls adaptive immune function and stimulates adrenocorticotropic hormone (ACTH) and PRL secretion. PRL maintains the function of the thymus and of the T cell-dependent adaptive immune system. The ACTH-adrenal axis stimulates natural immunity and of suppressor/regulatory T cells, which suppress the adaptive immune system. VP also has a direct effect on lymphoid cells, the significance of which remains to be elucidated. It is suggested that VP regulates the process of recovery from acute illness.
Collapse
Affiliation(s)
- Istvan Berczi
- Department of Immunology, Faculty of Medicine, the University of Manitoba, Winnipeg, Canada.
| | | | | |
Collapse
|
|
14
|
Combination of recombinant human growth hormone and propranolol decreases hypermetabolism and inflammation in severely burned children. Pediatr Crit Care Med 2008; 9:209-16. [PMID: 18477935 DOI: 10.1097/pcc.0b013e318166d414] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE Recombinant human growth hormone (rhGH) is a salutary modulator of posttraumatic metabolic responses. However, rhGH administration is associated with deleterious side effects, such as hyperglycemia, increased free fatty acids, and triglycerides, which limit its use. Administration of beta-blocker attenuates cardiac work and resting energy expenditure after severe thermal injury and improves fat metabolism and insulin sensitivity. Therefore, the combination of rhGH plus propranolol appears ideal. The aim of the present study was to determine whether rhGH plus propranolol improves hypermetabolism and the inflammatory and acute phase response after severe burn without causing adverse side effects. DESIGN Prospective randomized control trial. SETTING Shriners Hospitals for Children. PATIENTS Fifteen pediatric patients with burns > 40% total body surface area, 0.1-16 yrs of age, admitted within 7 days after burn. Fifteen children were matched for burn size, age, gender, inhalation injury, and infection and served as controls. INTERVENTIONS Patients in the experimental group received rhGH (0.2 mg/kg/day) and propranolol (to decrease heart rate by 15%) for > or = 15 days. MEASUREMENTS AND MAIN RESULTS Outcome measurements included resting energy expenditure, body composition, acute phase proteins, and cytokines. Both cohorts were similar in age, burn size, gender, and accompanying injuries. Percent predicted resting energy expenditure significantly decreased in patients receiving rhGH/propranolol (Delta -5% +/- 8%) compared with controls (Delta +35% +/- 20%) (p < .05). rhGH/propranolol administration significantly decreased serum C-reactive protein, cortisone, aspartate aminotransferase, alanine aminotransferase, free fatty acids, interleukin-6, interleukin-8, and macrophage inflammatory protein-1beta when compared with controls, while growth hormone/propranolol increased serum insulin-like growth factor-I, insulin-like growth factor binding protein-3, growth hormone, prealbumin, and interleukin-7 when compared with placebo (p < .05). CONCLUSIONS rhGH in combination with propranolol attenuates hypermetabolism and inflammation without the adverse side effects found with rhGH therapy alone.
Collapse
|
|
15
|
Norbury WB, Jeschke MG, Herndon DN. Metabolic Changes Following Major Burn Injury: How to Improve Outcome. Intensive Care Med 2007. [DOI: 10.1007/0-387-35096-9_48] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
|
|
16
|
The Effects of Gammahydroxybutyrate on Hypermetabolism and Wound Healing in a Rat Model of Large Thermal Injury. ACTA ACUST UNITED AC 2007; 63:1099-107. [DOI: 10.1097/ta.0b013e318157d9d0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
|
|
17
|
Jeschke MG, Herndon DN. The Hepatic Response to Severe Injury. Intensive Care Med 2007. [DOI: 10.1007/978-0-387-49518-7_58] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
|
|
18
|
An Y, Xiao YB. Growth hormone prevents acute liver injury induced by cardiopulmonary bypass in a rat model. J Thorac Cardiovasc Surg 2007; 134:342-50. [PMID: 17662771 DOI: 10.1016/j.jtcvs.2007.02.036] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2006] [Revised: 02/07/2007] [Accepted: 02/14/2007] [Indexed: 11/22/2022]
Abstract
OBJECTIVE Cardiopulmonary bypass-induced acute liver injury is a life-threatening complication thought to be associated with the inflammatory response and the acute-phase response. Recombinant human growth hormone can modulate the acute-phase response and inflammatory response. We tested the protective effect of growth hormone on cardiopulmonary bypass-induced liver injury in the rat. METHODS Adult male Sprague-Dawley rats (group G received 2.5 mg/kg recombinant human growth hormone intramuscularly at 8 am every 24 hours for 3 days and just before the initiation of cardiopulmonary bypass; group C served as a control group) underwent cardiopulmonary bypass (120 minutes, 120 mL x kg(-1) x min(-1), 34 degrees C) and were killed 3 hours after the termination of cardiopulmonary bypass. RESULTS Administration of recombinant human growth hormone markedly increased serum insulin-like growth factor and insulin-like growth factor-binding protein 3 levels compared with those seen in group C. Group G showed significantly lower serum concentrations of alanine aminotransferase and total bilirubin after cardiopulmonary bypass termination. Those receiving recombinant human growth hormone demonstrated a significant increase in serum prealbumin and transferrin levels and a marked decrease in serum amyloid A and C-reactive protein levels. Recombinant human growth hormone significantly decreased serum tumor necrosis factor alpha and interleukin 1beta levels, whereas no changes were found for serum interleukin 6 and interleukin 10 levels. Recombinant human growth hormone significantly increased total liver protein content and hepatocyte proliferation and decreased hepatocyte apoptosis versus values seen in group C. CONCLUSIONS These results suggest that growth hormone prevents cardiopulmonary bypass-induced acute liver injury in a rat model through decreases in acute-phase proteins, proinflammatory cytokines tumor necrosis factor alpha and interleukin 1beta, and hepatocyte apoptosis, which is associated with increases in constitutive hepatic proteins, total liver protein content, and hepatocyte proliferation. This strategy of pretreatment with growth hormone might be a prospective management for preventing acute liver injury when major cardiac surgery with cardiopulmonary bypass is performed.
Collapse
Affiliation(s)
- Yong An
- Department of Cardiovascular Surgery, Xin-Qiao Hospital, Third Military Medical University, Chongqing, China
| | | |
Collapse
|
|
19
|
Zheng H, Chen XL, Han ZX, Wang SY, Chen ZW. Effect of Ligustrazine on liver injury after burn trauma. Burns 2006; 32:328-34. [PMID: 16529867 DOI: 10.1016/j.burns.2005.10.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2005] [Indexed: 01/04/2023]
Abstract
This study was designed to investigate the effect of Ligustrazine on burn-induced liver injury as well as the activation of nuclear factor kappaB (NF-kappaB) in severely burned rats. Sprague-Dawley rats were divided into three groups: (1) sham group, rats who underwent sham burn; (2) control group, rats given third-degree burns over 30% total body surface area (TBSA) and lactated Ringer solution for resuscitation; (3) Ligustrazine group, rats given burn and lactated Ringer's solution with Ligustrazine inside for resuscitation. Liver injury was assessed at 24 h post-burn by serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as well as liver wet/dry weight ratio. Liver myeloperoxidase (MPO) activity was also analyzed. Hepatic NF-kappaB activity was examined by electrophoretic mobility shift assay (EMSA). Burn results in hepatic dysfunction and increased hepatic NF-kappaB activity, elevated liver wet/dry ratio and hepatic MPO activity. Ligustrazine inhibited these changes and alleviated burn-mediated hepatic dysfunction. The data indicated that Ligustrazine has a protective effect on burn-induced liver injury and possible mechanism may be attributed to its inhibitory action on the activation of NF-kappaB following burn trauma.
Collapse
Affiliation(s)
- Hong Zheng
- Department of Pathophysiology, Anhui Medical University, and Department of Burns, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230032, People's Republic of China
| | | | | | | | | |
Collapse
|
|
20
|
Pereira C, Murphy K, Jeschke M, Herndon DN. Post burn muscle wasting and the effects of treatments. Int J Biochem Cell Biol 2005; 37:1948-61. [PMID: 16109499 DOI: 10.1016/j.biocel.2005.05.009] [Citation(s) in RCA: 151] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2004] [Revised: 04/20/2005] [Accepted: 05/03/2005] [Indexed: 11/24/2022]
Abstract
Severe burns are typically followed by a hypermetabolic response that lasts for at least 9-12 months post-injury. The endocrine status is also markedly altered with an initial and then sustained increase in proinflammatory 'stress' hormones such as cortisol and other glucocorticoids, and catecholamines including epinephrine and norepinephrine by the adrenal medulla and cortex. These hormones exert catabolic effects leading to muscle wasting, the intensity of which depends upon the percentage of total body surface area (TBSA) involved, as well as the time elapsed since initial injury. Pharmacological and non-pharmacological strategies may be used to reverse the catabolic effect of thermal injury. Non-pharmacological strategies include early excision and wound closure of burn wound, aggressive treatment of sepsis, elevation of the environmental temperature to thermal neutrality (31.5+/-0.7 degrees C), high carbohydrate, high protein continuous enteral feeding and early institution of resistive exercise programs. Pharmacological modulators of the post-burn hypermetabolic response may be achieved through the administration of recombinant human growth hormone, low dose insulin infusion, use of the synthetic testosterone analogue, oxandrolone and beta blockade with propranolol. This paper aims to review the current understanding of post-burn muscle proteolysis and the effects of clinical and pharmacological strategies currently being studied to reverse it curb these debilitating sequelae of severe burns.
Collapse
Affiliation(s)
- Clifford Pereira
- Department of Surgery, The University of Texas Medical Branch and Shriners' Hospitals for Children, 815 Market Street, Galveston, TX 77550, USA
| | | | | | | |
Collapse
|
|
21
|
Pereira CT, Herndon DN. The pharmacologic modulation of the hypermetabolic response to burns. Adv Surg 2005; 39:245-61. [PMID: 16250555 DOI: 10.1016/j.yasu.2005.05.005] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Patients with burns less than 40% TBSA do not have catabolism unless sepsis develops. Those with burns more than 40% TBSA always experience catabolism, which causes metabolic derangements that persist for at least 1 year after the injury in most body tissues. The accomplishments of the past decade have placed us in the midst of an exciting paradigm shift from what used to be a primary concern (ie, mortality) to areas that are more likely to enhance the quality of life of burn survivors. Modulating postburn hypermetabolism for the burned patient is of overwhelming importance in both the immediate care stage and the rehabilitative stage. Postburn hypermetabolism cannot be completely reversed but may be manipulated by nonpharmacologic and pharmacologic means. Early burn wound excision and complete wound closure, prevention of sepsis, the maintenance of thermal neutrality for the patient by elevation of the ambient temperature, and graded resistance exercises during convalescence are simple, highly effective primary treatment goals. Although the initial burn injury and sepsis-related complications principally determine the extent of the metabolic response in burn victims, obligatory activity, background- and procedural-related pain, and anxiety also greatly increase metabolic rates. Judicious maximal narcotic support, appropriate sedation, and supportive psychotherapy are mandatory if their effects are to be minimized. Several anabolic and anticatabolic agents are available for use during immediate care and rehabilitation. Exogenous, continuous low-dose insulin infusion, beta-blockade with propranolol, and the use of the synthetic testosterone analogue oxandrolone are the most cost-effective and least toxic therapies to date. These greatly assist therapeutic minimization of the loss of lean body mass and linear growth delay and are effective in burned patients with and without sepsis. Adverse effects, cost benefits, and the ease of administration and monitoring must be examined when considering the possibility of their use.
Collapse
Affiliation(s)
- Clifford T Pereira
- Department of Surgery, University of Texas Medical Branch, Shriners Hospitals for Children, Galveston, Texas, USA
| | | |
Collapse
|
|
22
|
Castillo C, Salazar V, Ariznavarreta C, Vara E, Tresguerres JAF. Effect of growth hormone and estrogen administration on hepatocyte alterations in old ovariectomized female wistar rats. Endocrine 2005; 26:11-8. [PMID: 15805580 DOI: 10.1385/endo:26:1:011] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2004] [Revised: 12/17/2004] [Accepted: 12/17/2004] [Indexed: 12/21/2022]
Abstract
Aging could be due to the accumulation of oxidative damage. On the other hand, growth hormone (GH) and estrogen deficiency induce deleterious effects on different tissues, and hormonal replacement could counteract these effects. We have investigated whether GH and estrogen administration modify some parameters related to oxidative stress and inflammation in hepatocytes isolated from old ovariectomized female rats. Twenty-two month-old ovariectomized animals were divided into control rats, rats treated with GH, rats treated with estradiol, and rats treated with GH+estradiol. Two-month-old intact female rats were used as young reference group. Hepatocytes were isolated, cultured, and CO and NO release, ATP, cyclic-guanosyl monophosphate (cGMP), and lipid peroxide (LPO) content of cells, as well as phosphatidylcholine (PC)synthesis, were measured. Hepatocytes isolated from old ovariectomized rats showed a decrease in ATP content and PC synthesis compared to young rats. Age also induced an increase in LPO, NO, CO, and cGMP. Treating old rats with GH significantly increased ATP and reduced CO and cGMP levels. Estradiol administration improved all the parameters that were altered. Co-administration of GH and estrogens induced a more marked effect than estrogens alone only in cGMP content. In conclusion, administration of estrogens to old ovariectomized females seemed to prevent oxidative changes in hepatocytes, whereas the effect of GH is not so evident.
Collapse
Affiliation(s)
- Carmen Castillo
- Laboratory of Experimental Endocrinology, Department of Physiology, School of Medicine, Complutense University, Madrid, Spain
| | | | | | | | | |
Collapse
|
|
23
|
Beyea JA, Olson DM, Harvey S. Growth hormone (GH) action in the developing lung: Changes in lung proteins after adenoviral GH overexpression. Dev Dyn 2005; 234:404-12. [PMID: 16127721 DOI: 10.1002/dvdy.20538] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Growth hormone (GH) recently has been shown to be expressed in the neonatal rat lung during alveolarization. The possible functional importance of lung GH in lung function, therefore, has been assessed by determining changes in GH-responsive proteins in the developing rat lung after the overexpression of the GH gene in this tissue. GH overexpression was achieved using an adenovirus that expressed the mouse GH gene. This adenovirus was effective in inducing mouse GH expression in cultured rat lung L2 epithelial cells. It was also shown to be strongly expressed in the alveoli of 14-day-old rat pup lungs 10 days after it was administered by intratracheal injection, during a period of rapid lung development. Expression of the transgene in these pups was accompanied by changes in lung protein concentrations determined by two-dimensional gel electrophoresis and mass spectrometry. The lung concentrations of specific enzymes (nucleotide diphosphate kinase B, Cu/Zn superoxide dismutase, glutathione-S-transferase, and aldehyde reductase-1) were increased by the adenoviral expression of mouse GH, as were the concentrations of beta subunit G-protein calponin 2, beta-5 tubulin, retinoblastoma binding protein 4, and fetuin A. In contrast, the lung concentrations of haptoglobin and major acute phase alpha-1 protein were reduced by adenoviral expression of mouse GH. Although most of these proteins have not previously been identified as GH-responsive proteins, these results demonstrate actions of GH in the rat lung and support the possibility that GH acts as an autocrine/paracrine during early lung development.
Collapse
Affiliation(s)
- Jason A Beyea
- Department of Physiology and Perinatal Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | | | | |
Collapse
|
|
24
|
Radaković S, Surbatović M, Stanković N, Filipović N. [Changes in concentrations of sera proteins in war wound]. ACTA CHIRURGICA IUGOSLAVICA 2005; 52:59-64. [PMID: 16119316 DOI: 10.2298/aci0501059r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
UNLABELLED During the general reaction to trauma, substantional changes in protein composition of sera occure. The aim of the prospective study was to investigate net change in total protein and albumin concentrations, as well as albumin/globulin ratio in sera of war casualties during the first 14 posttraumatic days, and to establish the correlation between these changes and severity of trauma. Subjects were 79 war casualties. CONTROLS 33 blood donors. METHODS Injury severity was determined according to ISS and blood samples were collected 12 hours after trauma, then on the 1st, 2nd, 5th and 14th posttraumatic day. In war casualties values of total protein and albumin concentrations and albumin/globulin ratio were significantly decreased. Minimal concentrations were measured on 2nd posttraumatic day (589.04 g/l for total proteins, p; 36.66.21 g/l for albumins, p) or on 5th day (0.860.2 for albumin/globulin ratio, p). CONCLUSIONS During the acute-phase response to trauma, significant changes in concentration of total proteins, albumins and albumin/globulin ratio occure in sera of war casualties. These changes are the most promminent during the first 5 days, with tendency for normalization after that. Intensity of these changes depends of the severity of trauma.
Collapse
Affiliation(s)
- S Radaković
- Institut za higijenu ZPM, Vojnomedicinska akademija, Beograd
| | | | | | | |
Collapse
|
|
25
|
Castillo C, Salazar V, Ariznavarreta C, Vara E, Tresguerres JAF. Effect of recombinant human growth hormone on age-related hepatocyte changes in old male and female Wistar rats. Endocrine 2004; 25:33-9. [PMID: 15545704 DOI: 10.1385/endo:25:1:33] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2004] [Revised: 09/08/2004] [Accepted: 09/17/2004] [Indexed: 01/01/2023]
Abstract
Aging induces changes in several organs, such as the liver, and this process might be due to damage caused by free radicals and inflammatory mediators. The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis shows a reduction with age, and this fact could be associated with some age-related changes. The aim of this study was to investigate the effect of GH administration on age-induced alterations in hepatocytes. Two and twenty two month-old male and female Wistar rats were used. Old rats were treated with human recombinant GH for 10 wk. At the end of the treatment, hepatocytes were isolated from the liver and cultured, and different parameters were measured in cells and medium. Plasma IGF-1 was also measured. Aging significantly decreased plasma IGF-1 in males. In females, plasma IGF-1 was also reduced, but not significantly. GH treatment restored plasma IGF-1 levels to values similar to young males. Aging was associated with a significant increase in lipid peroxidation (LPO), nitric oxide (NO), carbon monoxide (CO) and cyclic guanosyl-monophosphate (cGMP), as well as a reduction in adenosyl triphosphate (ATP) and phosphatidylcholine (PC) synthesis. GH administration partially prevented all these changes in males. In females, some of the parameters were significantly improved by GH (ATP, CO, cGMP), while others showed a tendency to improvement, although differences did not reach significance. In conclusion, GH administration could exert beneficial effects against age-related changes in hepatocytes, mainly in males.
Collapse
Affiliation(s)
- Carmen Castillo
- Laboratory of Experimental Endocrinology, Department of Physiology, School of Medicine, Complutense University, Madrid, Spain
| | | | | | | | | |
Collapse
|
|
26
|
Wu X, Thomas SJ, Herndon DN, Sanford AP, Wolf SE. Insulin decreases hepatic acute phase protein levels in severely burned children. Surgery 2004; 135:196-202. [PMID: 14739855 DOI: 10.1016/j.surg.2003.08.018] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
BACKGROUND Severe burn induces the hepatic acute phase response. In this study, we wondered whether continuous insulin treatment decreases acute phase protein levels in the severely burned. METHODS Eighteen children aged 2 to 17 years with burns >40% of total body surface area were randomized to receive either insulin (n=9) or no treatment (n=9) within 72 hours after injury until the wounds were 95% healed. Insulin was given at a continuous rate of > or =1.5 microU/kg/min to maintain euglycemia (serum glucose 100-140 microg/dL). Plasma was examined at days 7, 14, 21, and 28 for acute phase protein levels including C-reactive protein, C3 complement, alpha1-acid glycoprotein, haptoglobin, alpha2-macroglobulin, prealbumin, transferrin, and retinol-binding protein. Statistical analysis was by ANOVA and t test. RESULTS With insulin treatment, alpha1-acid glycoprotein, C3 complement, alpha2-macroglobulin, and haptoglobin levels decreased (P<.05) after a severe burn compared with control, especially at days 21 and 28. Additionally, the hepatic constitutive proteins (prealbumin, transferrin, and retinol-binding protein) were lower in the insulin-treatment group than those of the control group at day 21 (P<.05). CONCLUSIONS Continuous insulin treatment decreases acute phase protein levels after a severe burn. The results suggest insulin downregulation of the hepatic acute phase response to injury.
Collapse
Affiliation(s)
- Xiaowu Wu
- Shriners Hospitals for Children and Department of Surgery, the University of Texas Medical Branch, Galveston, Tex 77550, USA
| | | | | | | | | |
Collapse
|
|
27
|
Dasu MRK, Cobb JP, Laramie JM, Chung TP, Spies M, Barrow RE. Gene expression profiles of livers from thermally injured rats. Gene 2004; 327:51-60. [PMID: 14960360 DOI: 10.1016/j.gene.2003.11.015] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2003] [Revised: 10/16/2003] [Accepted: 11/07/2003] [Indexed: 10/26/2022]
Abstract
The liver plays an important role in a severe thermal injury by modulating immune function, inflammatory processes and the acute phase response, which are an orchestrated attempt to restore homeostasis. Using high-density oligonucleotide arrays, we examined the gene expression profile in the livers of rats between 2 and 240 h after a 40% total body surface area (TBSA) burn. Alterations in gene expression unique to a thermal injury were identified. Approximately 39 genes out of 8700 genes on each array across all the time points showed a significant change in expression patterns. Real time reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analyses verified significant changes in early growth response-1 (Egr-1) messenger RNA (mRNA) and protein levels corresponding to the array data. Significant increases in serum levels of alpha-2-macroglobulin that correspond to changes in its mRNA levels were observed at 6 and 24 h after burn, p<0.05. The genomic pattern for liver in the hypermetabolic phase after the burn injury involves transcription factors, stress and inflammatory responses, cytoskeletal and extracellular matrix modifications, and regulation of cell proliferation and differentiation. During the initial phase of thermal injury gene expression profiles in the liver may provide some insight into how cellular protection mechanisms and systemic hypermetabolism are initiated and controlled. The genome wide changes observed may provide a rational therapeutic strategy to improve burn care.
Collapse
Affiliation(s)
- Mohan R K Dasu
- Shriners Hospitals for Children, 815 Market Street, Galveston, TX 77550, USA
| | | | | | | | | | | |
Collapse
|
|
28
|
Sheridan RL, Tompkins RG. What's new in burns and metabolism. J Am Coll Surg 2004; 198:243-63. [PMID: 14759783 DOI: 10.1016/j.jamcollsurg.2003.11.007] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2003] [Accepted: 11/10/2003] [Indexed: 12/31/2022]
Affiliation(s)
- Robert L Sheridan
- Burn Surgery Service, Shriners Hospital for Children, 51 Blossom Street, Boston, MA 02114, USA
| | | |
Collapse
|
|
29
|
Sun BW, Zhao XC, Wang GJ, Li N, Li JS. Changes of biological functions of dipeptide transporter (PepT1) and hormonal regulation in severe scald rats. World J Gastroenterol 2003; 9:2782-5. [PMID: 14669333 PMCID: PMC4612052 DOI: 10.3748/wjg.v9.i12.2782] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: To determine the regulatory effects of recombinant human growth hormone (rhGH) on dipeptide transport (PepT1) in normal and severe scald rats.
METHODS: Male Sprague-Dawley rats with 30% total body surface area (TBSA)IIIdegree scald were employed as the model. In this study rhGH was used at the dose of 2 IU.kg-1d-1. An everted sleeve of intestine 4 cm long obtained from mid-jejunum was securely incubated in Kreb’s solution with radioactive dipeptide (3H-glycylsarcosine, 3H-Gly-Sar, 10 μCi/ml) at 37 °C for 15 min to measure the effects of uptake and transport of PepT1 of small intestinal epithelial cells in normal and severe scald rats.
RESULTS: Abundant blood supply to intestine and mesentery was observed in normal and scald rats administered rhGH, while less supply of blood to intestine and mesentery was observed in rats without rhGH. Compared with controls, the transport of dipeptide in normal rats with injection of rhGH was not significantly increased (P = 0.1926), while the uptake was significantly increased (P = 0.0253). The effects of transport and uptake of PepT1 in scald rats with injection of rhGH were significantly increased (P = 0.0082, 0.0391).
CONCLUSION: Blood supply to intestine and mesentery of rats was increased following injection of rhGH. The effects of uptake and transport of dipeptide transporters in small intestinal epithelial cells of rats with severe scald were markedly up-regulated by rhGH.
Collapse
Affiliation(s)
- Bing-Wei Sun
- Department of General Surgery, School of Medicine, Nanjing University, Nanjing 210002, Jiangsu Province, China.
| | | | | | | | | |
Collapse
|
|
30
|
Sun BW, Zhao XC, Wang GJ, Li N, Li JS. Hormonal regulation of dipeptide transporter (PepT1) in Caco-2 cells with normal and anoxia/reoxygenation management. World J Gastroenterol 2003; 9:808-12. [PMID: 12679938 PMCID: PMC4611455 DOI: 10.3748/wjg.v9.i4.808] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the regulation effects of recombinant human growth hormone (rhGH) on dipeptide transporter (PepT1) in Caco-2 cells with normal culture and anoxia/reoxygenation injury.
METHODS: A human intestinal cell monolayer (Caco-2) was used as the in vitro model of human small intestine and cephalexin as the model substrate for dipeptide transporter (PepT1). Caco-2 cells grown on Transwell membrane filters were preincubated in the presence of rhGH in the culture medium for 4 d, serum was withdrawn from monolayers for 24 h before each experiment. The transport experiments of cephalexin across apical membromes were then conducted; Caco-2 cells grown on multiple well dishes (24 pore) with normal culture or anoxia/reoxygenation injury were preincubated with rhGH as above and uptake of cephalexin was then measured.
RESULTS: The transport and uptake of cephelaxin across apical membranes of Caco-2 cells after preincubation with rhGH were significantly increased compared with controls (P = 0.045, 0.0223). Also, addition of rhGH at physiological concentration (34 nM) to incubation medium greatly stimulates cephalexin uptake by anoxia/reoxygenation injuried Caco-2 cells (P = 0.0116), while the biological functions of PepT1 in injured Caco-2 cells without rhGH were markedly downregulated. Northern blot analysis showed that the level of PepT1 mRNA of rhGH-treated injured Caco-2 cells was greatly increased compared to controls.
CONCLUSION: The present results of rhGH stimulating the uptake and transport of cephalexin indicated that rhGH greatly upregulates the physiological effects of dipeptide transporters of Caco-2 cells. The alteration in the gene expression may be a mechanism of regulation of PepT1. In addition, Caco-2 cells take up cephalexin by the Proton-dependent dipeptide transporters that closely resembles the transporters present in the intestine. Caco-2 cells represent an ideal cellular model for future studies of the dipeptide transporter.
Collapse
Affiliation(s)
- Bing-Wei Sun
- Research Institute of General Surgery, Chinese PLA General Hospital of Nanjing Military Area, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, China.
| | | | | | | | | |
Collapse
|
|
31
|
Wu X, Herndon DN, Wolf SE. Growth hormone down-regulation of Interleukin-1beta and Interleukin-6 induced acute phase protein gene expression is associated with increased gene expression of suppressor of cytokine signal-3. Shock 2003; 19:314-20. [PMID: 12688541 DOI: 10.1097/00024382-200304000-00004] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Severe burn induces the hepatic acute phase response. We previously showed that recombinant human growth hormone (GH) treatment after burn down-regulated acute phase protein (APP) production and gene expression in vivo. In this study, we hypothesized that the inhibitory effect of GH on the hepatic acute phase response was due to increased suppressor of cytokine signaling (SOCS) gene expression. HepG2 cells were treated with Interleukin-1beta (IL-1beta; 2 ng/mL) and interleukin 6 (IL-6; 20 ng/mL) alone or combined with GH (2 microg/mL) for 15 and 30 min, and 1, 2, and 4 h. The levels of gene expression for alpha1-acid glycoprotein (AGP), alpha1-antitrypsin (ATT), and SOCS (CIS, SOCS-1, 2, and 3) were measured by reverse transcript-polymerase chain reaction (RT-PCR). APP levels in the supernatant were determined by enzyme-linked immunosorbent sandwich assay (ELISA). The gene expression of AGP and ATT were also measured in HepG2 cells transfected with pEF-Flag-l/mSOCS-3 plasmid after IL-1beta or IL-6 treatment. Data are expressed as means +/- SEM, and statistical analysis was performed by one- or two-way analysis of variance. IL-1beta and IL-6 induced AGP and ATT gene expression and protein production, respectively, which was down-regulated by GH treatment. SOCS-3 but not CIS, SOCS-1, or SOCS-2 gene expression was significantly increased by GH treatment. APP gene expression was significantly decreased in cells transfected with plasmid over expressing SOCS-3 after IL-6 and IL-1beta treatment. GH attenuates IL-1beta or IL-6 induced APP gene expression, which is associated with increased expression of SOCS-3. This study suggests that SOCS-3 plays an important role in the suppression of cytokine signaling by GH in down-regulating the acute phase response after injury.
Collapse
Affiliation(s)
- Xiaowu Wu
- Shriner's Hospitals for Children and Department of Surgery, University of Texas Medical Branch, Galveston, Texas 77550, USA
| | | | | |
Collapse
|
|
32
|
The acute phase response. ACTA ACUST UNITED AC 2003. [DOI: 10.1016/s1567-7443(03)80059-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
|
|
33
|
Wu XW, Spies M, Chappell VL, Herndon DN, Thompson JC, Wolf SE. Effect of bombesin on gut mucosal impairment after severe burn. Shock 2002; 18:518-22. [PMID: 12462559 DOI: 10.1097/00024382-200212000-00006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Severe cutaneous bum alters gut epithelial homeostasis. In previous studies, treatment with bombesin decreased mucosal atrophy and improved maintenance of gut mucosal integrity after severe burn. Our current hypothesis is that bombesin reduces burn-induced gut impairment by decreasing gut epithelial cell death. Fifty-four adult male Fisher-344 rats were randomly assigned to three groups: control, sham burn (I), burn (II), and burn + bombesin (III). Animals in groups II and III received a 60% total body surface area full thickness scald burn, and the treatment group (III) received bombesin subcutaneously (10 microg/kg, every 8 h) beginning immediately before the experiment. The proximal small bowel was harvested at 12 and 72 h after burn with measurement of wet and dry weight, mucosal weight, and protein content, and a 1-cm length of proximal end was excised and fixed in fomalin for histological and immunohistochemical observation. Data are expressed as means +/- SEM. Statistical analysis was by done by analysis of variance (significance at P < 0.05). Bombesin treatment attenuated mucosal atrophy demonstrated by restoration of the mucosal weight, mucosal protein content, and maintenance of mucosal height and total mucosal epithelial cell count. Gut epithelial cell apoptosis was, at least in part, inhibited by bombesin compared with a significant increase of gut cell apoptosis at 12 h after burn. Gut epithelial proliferation was not affected. Bombesin diminished burn-induced gut mucosal atrophy and gut epithelial cell apoptosis, suggesting that bombesin treatment may play an important role in the recovery of gut impairment after severe burn.
Collapse
Affiliation(s)
- Xiao-Wu Wu
- Shriner's Burns Hospital and Department of Surgery, University of Texas Medical Branch, Galveston, Texas 77550, USA
| | | | | | | | | | | |
Collapse
|
|
34
|
Jeschke MG, Low JF, Spies M, Vita R, Hawkins HK, Herndon DN, Barrow RE. Cell proliferation, apoptosis, NF-kappaB expression, enzyme, protein, and weight changes in livers of burned rats. Am J Physiol Gastrointest Liver Physiol 2001; 280:G1314-20. [PMID: 11352826 DOI: 10.1152/ajpgi.2001.280.6.g1314] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Thermal injury has been shown to alter gut epithelium and heart myocyte homeostasis by inducing programmed cell death. The effect of thermal injury on hepatocyte apoptosis and proliferation, however, has not been established. The purpose of this study was to determine whether a large thermal injury increases liver cell apoptosis and proliferation and whether these changes were associated with alterations in hepatic nuclear factor kappaB (NF-kappaB) expression and changes in liver enzymes and amount of protein. Sprague-Dawley rats received a 40% total body surface area scald burn or sham burn. Rats were killed and livers were harvested at 1, 2, 5, and 7 days after burn. Liver cell apoptosis was determined by terminal deoxyuridine nick end labeling (TUNEL) assay and cell proliferation by immunohistochemistry for proliferating cell nuclear antigen. Hepatic NF-kappaB expression was determined by Western blot, and total hepatic protein content was determined by protein assay. Protein concentration decreased after burn compared with sham controls (P < 0.05). Liver cell apoptosis, proliferation, and NF-kappaB expression in hepatocytes increased in burned rats compared with controls (P < 0.05). It was concluded that thermal injury induces hepatic cell apoptosis and proliferation associated with an increase in hepatic NF-kappaB expression and a decrease in hepatic protein concentration.
Collapse
Affiliation(s)
- M G Jeschke
- Shriners Hospital for Children and Department of Surgery, University Texas Medical Branch, 815 Market St., Galveston, TX 77550, USA
| | | | | | | | | | | | | |
Collapse
|
|
35
|
Jeschke MG, Barrow RE, Herndon DN. Recombinant human growth hormone treatment in pediatric burn patients and its role during the hepatic acute phase response. Crit Care Med 2000; 28:1578-84. [PMID: 10834715 DOI: 10.1097/00003246-200005000-00053] [Citation(s) in RCA: 65] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Recombinant human growth hormone (rHGH) has been shown to increase mortality in adult trauma patients; however, little has been reported on its side effects in children. The acute phase response has been suggested to be a contributing factor to trauma mortality. Therefore, the purpose of this study was to examine the effects of exogenous rHGH on the acute phase response in pediatric bum patients. DESIGN Prospective, randomized, double-blind study. SETTING Shriners Hospital for Children. PATIENTS Thermally injured pediatric patients, ranging in age from 0.1 to 16 yrs. INTERVENTIONS Twenty-eight thermally injured children received either 0.2 mg/kg/day of rHGH or saline (placebo) within 3 days of admission and for at least 25 days. MEASUREMENTS AND MAIN RESULTS Measurements were patient demographics, incidence of sepsis, inhalation injury, mortality, serum constitutive proteins, acute phase proteins, proinflammatory cytokines and insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein (IGFBP)-1, and IGFBP-3. No differences could be demonstrated in age, gender, burn size, incidence in sepsis (20% vs. 26%), inhalation injury (46% vs. 27%), or mortality (8% vs. 7%) between those receiving rHGH or placebo. Serum IGF-I and IGFBP-3 increased with rHGH treatment, whereas serum IGFBP-1 decreased compared with placebo (p < .05). Burned children treated with rHGH required significantly less albumin substitution to maintain normal levels compared with placebo (p < .05). Those receiving rHGH demonstrated a decrease in serum C-reactive protein and serum amyloid-A and an increase in serum retinol-binding protein compared with placebo (p < .05). rHGH decreased serum tumor necrosis factor-alpha and interleukin (IL)-1beta, whereas no changes were found for serum IL-1alpha, IL-6, and IL-10 compared with placebo (p < .05). Free fatty acids were elevated in burned children who received rHGH (p < .05). CONCLUSION Data indicate that rHGH does not increase mortality. rHGH decreased acute phase proteins, tumor necrosis factor-alpha, and IL-1beta, which is associated with increases in constitutive hepatic proteins and IGF-I.
Collapse
Affiliation(s)
- M G Jeschke
- Shriners Hospital for Children and Department of Surgery, University of Texas Medical Branch, Galveston, USA
| | | | | |
Collapse
|
|
36
|
Jeschke MG, Chrysopoulo MT, Herndon DN, Wolf SE. Increased expression of insulin-like growth factor-I in serum and liver after recombinant human growth hormone administration in thermally injured rats. J Surg Res 1999; 85:171-7. [PMID: 10383855 DOI: 10.1006/jsre.1999.5623] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND Recombinant human growth hormone (rhGH) has been shown to modulate the hypermetabolic response and the hepatic acute-phase response after thermal injury. In vitro studies, however, demonstrated that rhGH activates insulin-like growth factor-I (IGF-I) gene transcription and production, suggesting that rhGH may exert some of its effects indirectly through IGF-I stimulation. The purpose of this study was to determine the effects of rhGH on serum and hepatic IGF-I in thermally injured rats. METHODS Sprague-Dawley rats (56 males) receiving a 60% TBSA third-degree scald burn were randomly divided to receive either rhGH (2.5 mg/kg/day im) or saline (control). Rats were sacrificed on postburn days 1, 2, 5, and 7 and serum IGF-I, hepatic IGF-I mRNA, and IGF-I protein concentration were measured. The physiologic response to changes in IGF-I levels was evaluated by measuring hepatocyte proliferation, total liver protein concentration, and muscle dry/wet weights. RESULTS Serum IGF-I was increased from postburn day 1 through day 7 in rats receiving rhGH compared to controls (P < 0.05). Hepatic IGF-I mRNA and IGF-I protein expression were increased from day 1 to 7 after burn in animals receiving rhGH when compared to controls (P < 0.05). Recombinant hGH increased hepatocyte proliferation at 5 days and total liver protein concentration at 5 and 7 days postburn compared to controls (P < 0.05). Muscle dry/wet weights increased in rats receiving rhGH at 7 days after burn compared to controls (P < 0.05). SUMMARY Liver and serum IGF-I levels decreased after a thermal injury. Recombinant hGH attenuated this decrease by stimulating hepatic IGF-I expression. Increases in IGF-I were associated with increases in hepatocyte proliferation and protein concentration in liver and muscle. CONCLUSION We suggest that rhGH modulates the hypermetabolic response through IGF-I stimulation in the hepatic parenchyma.
Collapse
Affiliation(s)
- M G Jeschke
- Department of Surgery, University of Texas Medical Branch, Galveston, Texas, 77550, USA
| | | | | | | |
Collapse
|