|
1
|
Mulder PPG, Hooijmans CR, Vlig M, Middelkoop E, Joosten I, Koenen HJPM, Boekema BKHL. Kinetics of Inflammatory Mediators in the Immune Response to Burn Injury: Systematic Review and Meta-Analysis of Animal Studies. J Invest Dermatol 2024; 144:669-696.e10. [PMID: 37806443 DOI: 10.1016/j.jid.2023.09.269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 08/31/2023] [Accepted: 09/20/2023] [Indexed: 10/10/2023]
Abstract
Burns are often accompanied by a dysfunctional immune response, which can lead to systemic inflammation, shock, and excessive scarring. The objective of this study was to provide insight into inflammatory pathways associated with burn-related complications. Because detailed information on the various inflammatory mediators is scattered over individual studies, we systematically reviewed animal experimental data for all reported inflammatory mediators. Meta-analyses of 352 studies revealed a strong increase in cytokines, chemokines, and growth factors, particularly 19 mediators in blood and 12 in burn tissue. Temporal kinetics showed long-lasting surges of proinflammatory cytokines in blood and burn tissue. Significant time-dependent effects were seen for IL-1β, IL-6, TGF-β1, and CCL2. The response of anti-inflammatory mediators was limited. Burn technique had a profound impact on systemic response levels. Large burn size and scalds further increased systemic, but not local inflammation. Animal characteristics greatly affected inflammation, for example, IL-1β, IL-6, and TNF-α levels were highest in young, male rats. Time-dependent effects and dissimilarities in response demonstrate the importance of appropriate study design. Collectively, this review presents a general overview of the burn-induced immune response exposing inflammatory pathways that could be targeted through immunotherapy for burn patients and provides guidance for experimental set-ups to advance burn research.
Collapse
Affiliation(s)
- Patrick P G Mulder
- Preclinical Research, Association of Dutch Burn Centres (ADBC), Beverwijk, The Netherlands; Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
| | - Carlijn R Hooijmans
- Meta-Research Team, Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Marcel Vlig
- Preclinical Research, Association of Dutch Burn Centres (ADBC), Beverwijk, The Netherlands
| | - Esther Middelkoop
- Preclinical Research, Association of Dutch Burn Centres (ADBC), Beverwijk, The Netherlands; Department of Plastic, Reconstructive and Hand Surgery, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Tissue Function and Regeneration, Amsterdam Movement Sciences, Amsterdam, The Netherlands
| | - Irma Joosten
- Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Hans J P M Koenen
- Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Bouke K H L Boekema
- Preclinical Research, Association of Dutch Burn Centres (ADBC), Beverwijk, The Netherlands; Department of Plastic, Reconstructive and Hand Surgery, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| |
Collapse
|
|
2
|
Sleeve gastrectomy-induced endocrine changes in the remnant stomachs of premenopausal and postmenopausal rats: role of the estrogen receptors. Surg Obes Relat Dis 2020; 17:193-207. [PMID: 33011072 DOI: 10.1016/j.soard.2020.08.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 08/02/2020] [Accepted: 08/12/2020] [Indexed: 12/28/2022]
Abstract
BACKGROUND Although alterations in the plasma levels of leptin, glucagon-like peptide-1, and gastrin were linked with bariatric surgery outcomes, gastric production of these peptides was not elucidated before. OBJECTIVE The aim was to evaluate the impact of estrogen depletion and estrogen receptors (ERs) on sleeve gastrectomy (SG)-induced alterations in gastric hormone production, gastric mucosal integrity, and bone mass. SETTING Physiology Research Lab at the University. METHODS Female Sprague-Dawley rats underwent ovariectomy or sham operation (control), and 2 months later SG or sham SG was performed. Rats received either nonselective agonist 17 β, ER-α agonist, ER-β agonist, or vehicle for 3 weeks. Trunk blood and gastric tissues were collected for biochemical measurements, while histopathologic examination was performed in gastric and femur samples. RESULTS In the presence of intact ovaries, SG-induced weight loss was accompanied by reductions in the gastric synthesis of leptin and gastrin, while gastric glucagon-like peptide-1 was additionally decreased when SG was performed at the postmenopausal state. SG elevated the depleted serum estradiol levels of menopause, implicating a beneficial effect, but the occurrence of severe gastric mucosal injury was triggered. On the other hand, using ER agonists upregulated gastrin-expressing cells, ameliorated gastric injury, and improved bone loss. CONCLUSIONS SG, either at premenopausal or postmenopausal state, resulted in considerable loss in bone mass, along with reductions in the gastric levels of gastrin and leptin. Functional status of the ovaries needs to be taken into consideration when monitoring the outcomes of SG, and ER agonists could be of value in controlling SG-induced complications.
Collapse
|
|
3
|
Şen LS, Özdemir Kumral ZN, Memi G, Ercan F, Yeğen BC, Yeğen C. The gastroprotective effect of obestatin on indomethacin-induced acute ulcer is mediated by a vagovagal mechanism. Physiol Int 2020; 107:243-255. [PMID: 32692714 DOI: 10.1556/2060.2020.00025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 02/17/2020] [Indexed: 12/12/2022]
Abstract
In order to investigate the role of the vagus nerve in the possible gastroprotective effect of obestatin on the indomethacin-induced acute oxidative gastric injury, Sprague-Dawley rats of both sexes were injected subcutaneously with indomethacin (25 mg/kg, 5% NaHCO3) followed by obestatin (10, 30 or 100 μg/kg). In other sets of rats, surgical vagotomy (Vx) or selective degeneration of vagal afferent fibers by perivagal capsaicin was performed before the injections of indomethacin or indomethacin + obestatin (30 μg/kg). Gastric serosal blood flow was measured, and 4 h after ulcer induction gastric tissue samples were taken for histological and biochemical assays. Obestatin reduced the severity of indomethacin-induced acute ulcer via the reversal of reactive hyperemia, by inhibiting ulcer-induced neutrophil infiltration and lipid peroxidation along with the replenishment of glutathione (GSH) stores, whereas Vx abolished the inhibitory effect of obestatin on blood flow and lipid peroxidation, and worsened the severity of ulcer. On the other hand, serosal blood flow was even amplified by the selective denervation of the capsaicin-sensitive vagal afferent fibers, but obestatin-induced reduction in ulcer severity was not altered. In conclusion, the gastroprotective effect of obestatin on indomethacin-induced ulcer appears to involve the activation of the vagovagal pathway.
Collapse
Affiliation(s)
- Leyla Semiha Şen
- 1Department of Physiology, Marmara University School of Medicine, İstanbul, Turkey.,3Department of General Surgery, Marmara University School of Medicine, İstanbul, Turkey
| | | | - Gülsün Memi
- 1Department of Physiology, Marmara University School of Medicine, İstanbul, Turkey
| | - Feriha Ercan
- 2Department of Histology & Embryology, Marmara University School of Medicine, İstanbul, Turkey
| | - Berrak C Yeğen
- 1Department of Physiology, Marmara University School of Medicine, İstanbul, Turkey
| | - Cumhur Yeğen
- 3Department of General Surgery, Marmara University School of Medicine, İstanbul, Turkey
| |
Collapse
|
|
4
|
Gorduza D, Plotton I, Remontet L, Gay CL, El Jani M, Cheikhelard A, Blanc T, El Ghoneimi A, Leclair MD, Roy P, Pirot F, Mimouni Y, Gaillard S, Chatelain P, Morel Y, Kassai B, Mouriquand P. Preoperative Topical Estrogen Treatment vs Placebo in 244 Children With Midshaft and Posterior Hypospadias. J Clin Endocrinol Metab 2020; 105:5835305. [PMID: 32386308 DOI: 10.1210/clinem/dgaa231] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 05/06/2020] [Indexed: 02/05/2023]
Abstract
PURPOSE Urethral fistula and dehiscence are common after hypospadias surgery. Preoperative androgens have been considered to reduce these complications although this consideration is not evidence-based. Dermatologists have reported the benefits of topical estrogens on skin healing. We investigated whether the preoperative use of topical promestriene could reduce healing complications in hypospadias surgery. Our primary objective was to demonstrate a reduction of healing complications with promestriene vs placebo. Impact on reoperations and other complications, clinical tolerance, bone growth, and biological systemic effects of the treatment were also considered. METHODS We conducted a prospective, randomized, placebo-controlled, double-blind, parallel group trial between 2011 and 2015 in 4 French centers. One-stage transverse preputial island flap urethroplasty (onlay urethroplasty) was selected for severe hypospadias. Promestriene or placebo was applied on the penis for 2 months prior to surgery. The primary outcome was the presence of postoperative urethral fistula or dehiscence in the first year postsurgery. For safety reasons, hormonal and anatomical screenings were performed. RESULTS Out of 241 patients who received surgery, 122 patients were randomized to receive placebo, and 119 patients received promestriene. The primary outcome was unavailable for 11 patients. Healing complications were assessed at 16.4% (19/116) in the placebo vs 14.9% (17/114) in the promestriene arm, and the odds ratio adjusted on center was 0.93 (95% confidence interval 0.45-1.94), P = 0.86. CONCLUSIONS AND RELEVANCE Although we observed an overall lower risk of complications compared to previous publications, postsurgery complications were not different between promestriene and placebo, because of a lack of power of the study or the inefficacy of promestriene.
Collapse
Affiliation(s)
- Daniela Gorduza
- Centre de Référence Maladies Rares Développement Génital: du Fœtus à l'Adulte, Hospices Civils de Lyon, Bron, France
- Service de Chirurgie Uro-Viscérale de l'Enfant-Hôpital Mère Enfant, Hospices Civils de Lyon, Bron, France
| | - Ingrid Plotton
- Centre de Référence Maladies Rares Développement Génital: du Fœtus à l'Adulte, Hospices Civils de Lyon, Bron, France
- Service d'Endocrinologie Pédiatrique, Hôpital Mère-Enfant, Centre Hospitalo-Universitaire de Lyon, Bron Cedex, France
| | - Laurent Remontet
- Université de Lyon, Lyon, France
- Université Lyon 1; CNRS, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Villeurbanne, France
- Hospices Civils de Lyon, Service de Biostatistiques, Lyon, France
| | - Claire-Lise Gay
- Centre de Référence Maladies Rares Développement Génital: du Fœtus à l'Adulte, Hospices Civils de Lyon, Bron, France
- Service d'Endocrinologie Pédiatrique, Hôpital Mère-Enfant, Centre Hospitalo-Universitaire de Lyon, Bron Cedex, France
| | - Meriem El Jani
- Hospices Civils de Lyon, EPICIME-CIC 1407 de Lyon, Inserm, Department of Clinical Epidemiology, Bron, France
- Université de Lyon, Lyon, France
| | - Alaa Cheikhelard
- Service de chirurgie viscérale et urologie pédiatrique, APHP, Hôpital Necker, Paris, France; Université Sorbonne Paris cité, Paris, France
| | - Thomas Blanc
- Service de chirurgie viscérale et urologie pédiatrique, APHP, Hôpital Necker, Paris, France; Université Sorbonne Paris cité, Paris, France
| | - Alaa El Ghoneimi
- Service de chirurgie viscérale et urologie pédiatrique, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Hôpital Robert Debré, APHP, Université Paris Diderot, Paris, France
| | - Marc-David Leclair
- Service de chirurgie pédiatrique, CHU de Nantes, Nantes, Loire Atlantique, France
| | - Pascal Roy
- Université de Lyon, Lyon, France
- Hospices Civils de Lyon, Service de Biostatistiques, Lyon, France
| | - Fabrice Pirot
- Service pharmaceutique, Plateforme FRIPHARM, Groupement Hospitalier Edouard Herriot, Lyon Cedex, France
- Laboratoire de Recherche et Développement de Pharmacie Galénique Industrielle, Plateforme FRIPHARM, Faculté de Pharmacie, Laboratoire de Biologie Tissulaire et Ingénierie Thérapeutique - UMR 5305, Université Claude Bernard Lyon 1, Lyon Cedex, France
| | - Yanis Mimouni
- Hospices Civils de Lyon, EPICIME-CIC 1407 de Lyon, Inserm, Department of Clinical Epidemiology, Bron, France
- Université de Lyon, Lyon, France
| | - Segolene Gaillard
- Hospices Civils de Lyon, EPICIME-CIC 1407 de Lyon, Inserm, Department of Clinical Epidemiology, Bron, France
- Université de Lyon, Lyon, France
| | - Pierre Chatelain
- Centre de Référence Maladies Rares Développement Génital: du Fœtus à l'Adulte, Hospices Civils de Lyon, Bron, France
- Service d'Endocrinologie Pédiatrique, Hôpital Mère-Enfant, Centre Hospitalo-Universitaire de Lyon, Bron Cedex, France
| | - Yves Morel
- Centre de Référence Maladies Rares Développement Génital: du Fœtus à l'Adulte, Hospices Civils de Lyon, Bron, France
- Laboratoire d'Hormonologie d'Endocrinologie Moléculaire et des Maladies Rares, INSERM 1208, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France
| | - Behrouz Kassai
- Hospices Civils de Lyon, EPICIME-CIC 1407 de Lyon, Inserm, Department of Clinical Epidemiology, Bron, France
- Université de Lyon, Lyon, France
| | - Pierre Mouriquand
- Centre de Référence Maladies Rares Développement Génital: du Fœtus à l'Adulte, Hospices Civils de Lyon, Bron, France
- Service de Chirurgie Uro-Viscérale de l'Enfant-Hôpital Mère Enfant, Hospices Civils de Lyon, Bron, France
- Université Claude-Bernard-Lyon 1, Lyon, France
| |
Collapse
|
|
5
|
Ercan G, Ilbar Tartar R, Solmaz A, Gulcicek OB, Karagulle OO, Meric S, Cayoren H, Kusaslan R, Kemik A, Gokceoglu Kayali D, Cetinel S, Celik A. Potent therapeutic effects of ruscogenin on gastric ulcer established by acetic acid. Asian J Surg 2019; 43:405-416. [PMID: 31345657 DOI: 10.1016/j.asjsur.2019.07.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 06/13/2019] [Accepted: 07/01/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND/OBJECTIVE The present study investigated the potent therapeutic effects of Ruscogenin, main steroid sapogenin of traditional Chinese plant called 'Ophiopogon japonicas', on chronic ulcer model established with acetic acid in rats. METHODS 24 rats were attenuated to the sham (2 ml/kg/day isotonic solution), control (untreated ulcer) and treatment (3 ml/kg/day ruscogenin) groups. After treatment for 2 weeks, gastric tissues were collected and prepared for light microscopic (H&E), immunohistochemical (Collagen I, III and IV) and biochemical analysis [Epidermal growth factor (EGF), Prostaglandin E2 (PGE2), Tumor Necrosis Factor alpha (TNF-α), Interleukin 6 and 8 (IL-6 and IL-8), Lipid Peroxidase (LPO), Myeloperoxidase (MPO), Glutathione (GSH) and Glutathione Peroxidase (GSH-Px)] and transmission electron microscopy (TEM). RESULTS Macroscopic scoring showed that the ulceration area of ruscogenin-treated group decreased compared with control group. Immunohistochemical analysis revealed ruscogenin ameliorated and restored the levels of Collagen I and IV to the levels of sham group. Tissue levels of EGF and PGE2 enhanced significantly in untreated ulcer group while were higher in treated ulcer group than the control group. TNF-α, IL-6, IL-8, LPO, MPO levels increased significantly in control group whereas decreased in treated rats after ruscogenin treatment. However, levels of GSH and GSH-Px increased significantly in treatment group. TEM showed chief cells and parietal cells of ulcer group having degenerated organelles while ruscogenin group had normal ultrastructure of cells. CONCLUSION There are potent anti-inflammatory and anti-oxidant effects of ruscogenin on gastric ulcer and may be successfully used as a safe and therapeutic agent in treatment of peptic ulcer.
Collapse
Affiliation(s)
- Gulcin Ercan
- Department of General Surgery, University of Health Science Bagcilar Training and Research Hospital, Istanbul, Turkey.
| | - Rumeysa Ilbar Tartar
- Department of General Surgery, University of Health Science Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Ali Solmaz
- Department of General Surgery, University of Health Science Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Osman Bilgin Gulcicek
- Department of General Surgery, University of Health Science Bagcilar Training and Research Hospital, Istanbul, Turkey
| | | | - Serhat Meric
- Department of General Surgery, University of Health Science Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Huseyin Cayoren
- Department of General Surgery, University of Health Science Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Ramazan Kusaslan
- Department of General Surgery, University of Health Science Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Ahu Kemik
- Department of Biochemistry Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Damla Gokceoglu Kayali
- Department of Histology and Embryology, Faculty of Medicine, Marmara University, Istanbul, Turkey
| | - Sule Cetinel
- Department of Histology and Embryology, Faculty of Medicine, Marmara University, Istanbul, Turkey
| | - Atilla Celik
- Department of General Surgery, University of Health Science Bagcilar Training and Research Hospital, Istanbul, Turkey
| |
Collapse
|
|
6
|
Huang HH, Lee YC, Chen CY. Effects of burns on gut motor and mucosa functions. Neuropeptides 2018; 72:47-57. [PMID: 30269923 DOI: 10.1016/j.npep.2018.09.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 08/16/2018] [Accepted: 09/19/2018] [Indexed: 02/08/2023]
Abstract
This review analyzed the published studies on the effects of thermal injury on gastrointestinal motility and mucosal damage. Our strategy was to integrate all available evidence to provide a complete review on the prokinetic properties of variable reagents and the potential clinical treatment of mucosal damage and gastrointestinal dysmotility after thermal injury. We classified the studies into two major groups: studies on gastrointestinal dysmotility and studies on mucosal damage. We also subclassified the studies into 3 parts: stomach, small intestine, and colon. This review shows evidence that ghrelin can recover burn-induced delay in gastric emptying and small intestinal transit, and can protect the gastric mucosa from burn-induced injury. Oxytocin and β-glucan reduced the serum inflammatory mediators, and histological change and mucosal damage indicators, but did not show evidence of having the ability to recover gastrointestinal motility. Using a combination of different reagents to protect the gastrointestinal mucosa against damage and to recover gastrointestinal motility is an alternative treatment for thermal injury.
Collapse
Affiliation(s)
- Hsien-Hao Huang
- Department of Emergency Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Yu-Chi Lee
- Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan
| | - Chih-Yen Chen
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Taiwan Association for the Study of Small Intestinal Diseases, Guishan, Taiwan.
| |
Collapse
|
|
7
|
Abstract
In the present study, we aimed to explore the time course pathological changes after burn injury. The time course microarray data of burn injury from the Gene Expression Omnibus (GEO) was further analyzed through bioinformatics analysis. The differential expression genes (DEGs) were identified in the early-stage vs. control groups, middle-stage vs. control groups, and early-stage vs. middle-stage groups after burn injury, followed by pathway enrichment analysis. Gene modules associated with burn injury progression were identified through weighted gene co-expression network analysis (WGCNA), and hub genes were identified via network topology analysis. There were a total of 745 DEGs in the early vs. control group, 1104 DEGs in mid vs. control, and 61 DEGs in early vs. mid group. The significant pathways enriched by DEGs in the middle stage were also enriched by DEGs in the early stage. Immunodeficiency was a significant pathway specific for the DEGs in the early stage. There were 19 overlapped genes, such as myeloperoxidase, transcobalamin, and interferon-induced protein with tetratricopeptide repeats 1, among DEGs in early vs. control, middle vs. control, and early vs. middle groups. WGCNA identified three gene modules that were significantly associated with burn injury progression. Furthermore, we identified several gene modules and biological processes that might be associated with burn injury progression, and such results may be beneficial in understanding the underlying mechanisms and developing novel drugs.
Collapse
|
|
8
|
Al-Tarrah K, Moiemen N, Lord JM. The influence of sex steroid hormones on the response to trauma and burn injury. BURNS & TRAUMA 2017; 5:29. [PMID: 28920065 PMCID: PMC5597997 DOI: 10.1186/s41038-017-0093-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 07/19/2017] [Indexed: 12/24/2022]
Abstract
Trauma and related sequelae result in disturbance of homeostatic mechanisms frequently leading to cellular dysfunction and ultimately organ and system failure. Regardless of the type and severity of injury, gender dimorphism in outcomes following trauma have been reported, with females having lower mortality than males, suggesting that sex steroid hormones (SSH) play an important role in the response of body systems to trauma. In addition, several clinical and experimental studies have demonstrated the effects of SSH on the clinical course and outcomes following injury. Animal studies have reported the ability of SSH to modulate immune, inflammatory, metabolic and organ responses following traumatic injury. This indicates that homeostatic mechanisms, via direct and indirect pathways, can be maintained by SSH at local and systemic levels and hence result in more favourable prognosis. Here, we discuss the role and mechanisms by which SSH modulates the response of the body to injury by maintaining various processes and organ functions. Such properties of sex hormones represent potential novel therapeutic strategies and further our understanding of current therapies used following injury such as oxandrolone in burn-injured patients.
Collapse
Affiliation(s)
- K Al-Tarrah
- Institute of Inflammation and Ageing, Birmingham University Medical School, B15 2TT, Birmingham, UK.,Scar Free Foundation Centre for Burns Research, University Hospital Birmingham Foundation Trust, B15 2WB, Birmingham, UK
| | - N Moiemen
- Scar Free Foundation Centre for Burns Research, University Hospital Birmingham Foundation Trust, B15 2WB, Birmingham, UK
| | - J M Lord
- Institute of Inflammation and Ageing, Birmingham University Medical School, B15 2TT, Birmingham, UK
| |
Collapse
|
|
9
|
Özdemir Kumral ZN, Kolgazi M, Üstünova S, Kasımay Çakır Ö, Çevik ÖD, Şener G, Yeğen BÇ. Estrogen receptor agonists alleviate cardiac and renal oxidative injury in rats with renovascular hypertension. Clin Exp Hypertens 2016; 38:500-9. [DOI: 10.3109/10641963.2015.1116550] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
| | - Meltem Kolgazi
- Acibadem University School of Medicine, Department of Physiology, Istanbul, Turkey
| | - Savaş Üstünova
- Bezmialem Vakıf University School of Medicine, Department of Physiology, Istanbul, Turkey
| | - Özgür Kasımay Çakır
- Marmara University School of Medicine, Department of Physiology, Istanbul, Turkey
| | - Özge Dağdeviren Çevik
- Cumhuriyet University Faculty of Pharmacy, Department of Biochemistry, Sivas, Turkey
| | - Göksel Şener
- Marmara University Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey
| | - Berrak Ç. Yeğen
- Marmara University School of Medicine, Department of Physiology, Istanbul, Turkey
| |
Collapse
|
|
10
|
Role of gender in burn-induced heterotopic ossification and mesenchymal cell osteogenic differentiation. Plast Reconstr Surg 2015; 135:1631-1641. [PMID: 26017598 DOI: 10.1097/prs.0000000000001266] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
BACKGROUND Heterotopic ossification most commonly occurs after burn injury, joint arthroplasty, and trauma. Male gender has been identified as a risk factor for the development of heterotopic ossification. It remains unclear why adult male patients are more predisposed to this pathologic condition than adult female patients. In this study, the authors use their validated tenotomy/burn model to explore differences in heterotopic ossification between male and female mice. METHODS The authors used their Achilles tenotomy and burn model to evaluate the osteogenic potential of mesenchymal stem cells of male and female injured and noninjured mice. Groups consisted of injured male (n = 3), injured female (n = 3), noninjured male (n = 3), and noninjured female (n = 3) mice. The osteogenic potential of cells harvested from each group was assessed through RNA and protein levels and quantified using micro-computed tomographic scan. Histomorphometry was used to verify micro-computed tomographic findings, and immunohistochemistry was used to assess osteogenic signaling at the site of heterotopic ossification. RESULTS Mesenchymal stem cells of male mice demonstrated greater osteogenic gene and protein expression than those of female mice (p < 0.05). Male mice in the burn group formed 35 percent more bone than female mice in the burn group. This bone formation correlated with increased pSmad and insulin-like growth factor 1 signaling at the heterotopic ossification site in male mice. CONCLUSIONS The authors demonstrate that male mice form quantitatively more bone compared with female mice using their burn/tenotomy model. These findings can be explained at least in part by differences in bone morphogenetic protein and insulin-like growth factor 1 signaling.
Collapse
|
|
11
|
Opposite Expression of SPARC between the Liver and Pancreas in Streptozotocin-Induced Diabetic Rats. PLoS One 2015; 10:e0131189. [PMID: 26110898 PMCID: PMC4481468 DOI: 10.1371/journal.pone.0131189] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Accepted: 05/30/2015] [Indexed: 12/30/2022] Open
Abstract
Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that regulates several cellular events, including inflammation and tissue remodelling. In this study, we investigated the tissue-specific expression of SPARC in streptozotocin (STZ)-induced diabetes, and found that SPARC was significantly up-regulated in the liver while down-regulated in the pancreas of STZ-induced diabetic rats. Chronic inflammation occurred in the diabetic pancreas accompanied by up-regulation of CCAAT/enhancer-binding protein beta (C/EBPβ) and its targets (TNFα, Il6, CRP, and Fn1) as well as myeloperoxidase (Mpo) and C-X-C chemokine receptor type 2 (Cxcr2). Diabetic liver showed significant up-regulation of Tgfb1 as well as moderately less up-regulated TNFα and reduced Fn1, resulting in elevated fibrogenesis. PARP-1 was not up-regulated during CD95-mediated apoptosis, resulting in restoration of high ATP levels in the diabetic liver. On the contrary, CD95-dependent apoptosis was not observed in the diabetic pancreas due to up-regulation of PARP-1 and ATP depletion, resulting in necrosis. The cytoprotective machinery was damaged by pancreatic inflammation, whereas adequate antioxidant capacity indicates low oxidative stress in the diabetic liver. High and low cellular insulin content was found in the diabetic liver and pancreas, respectively. Furthermore, we identified six novel interacting partner proteins of SPARC by co-immunoprecipitation in the diabetic liver and pancreas, and their interactions with SPARC were predicted by bioinformatics tools. Taken together, opposite expression of SPARC in the diabetic liver and pancreas may be related to inflammation and immune cell infiltration, degrees of apoptosis and fibrosis, cytoprotective machinery, and cellular insulin levels.
Collapse
|
|
12
|
Estrogen alleviates acetic acid-induced gastric or colonic damage via both ERα- and ERβ-mediated and direct antioxidant mechanisms in rats. Inflammation 2015; 37:694-705. [PMID: 24323397 DOI: 10.1007/s10753-013-9786-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In order to demonstrate the possible protective effects of estrogen receptor (ER)-α and ERβ receptor subtypes in the pathogenesis of colonic and gastric oxidant damage, experimental ulcer and colitis were induced by acetic acid, and the animals were randomly divided as colitis, ulcer, and their corresponding non-ulcer and non-colitis control groups. Each group of rats was treated intramuscularly with the vehicle, selective ERα agonist propylpyrazole-triol (1 mg/kg), ERβ agonist diarylpropionitrile (1 mg/kg), non-selective ER agonist 17β estradiol (E2; 1 mg/kg), or E2 plus non-selective ER antagonist ICI-182780 (1 mg/kg). The results revealed that induction of ulcer or colitis resulted in systemic inflammation as assessed by increased levels of plasma TNF-α and IL-6 levels. In both tissues, the presence of oxidant damage was verified by histological analysis and elevated myleoperoxidase activity. In the colitis and ulcer groups, both ER agonists and the non-selective E2 reversed the oxidative damage in a similar manner. These findings indicate that estrogen acts via both ERα- and ERβ-mediated and direct antioxidant mechanisms, where both ER subtypes play equal and efficient roles in the anti-inflammatory action of estrogen, in limiting the migration of neutrophils to the inflamed tissue, reducing the release and activation of cytokines and thereby alleviating tissue damage.
Collapse
|
|
13
|
Romana-Souza B, Assis de Brito TL, Pereira GR, Monte-Alto-Costa A. Gonadal hormones differently modulate cutaneous wound healing of chronically stressed mice. Brain Behav Immun 2014; 36:101-10. [PMID: 24157428 DOI: 10.1016/j.bbi.2013.10.015] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2013] [Revised: 09/26/2013] [Accepted: 10/15/2013] [Indexed: 12/17/2022] Open
Abstract
Gonadal hormones influence physiological responses to stress and cutaneous wound healing. The aim of this study was to investigate the role of gonadal hormones on cutaneous wound healing in chronically stressed mice. Male and female mice were gonadectomized, and after 25 days, they were spun daily at 115 rpm for 15 min every hour until euthanasia. Twenty-eight days after the gonadectomy, an excisional lesion was created. The animals were killed 7 or 14 days after wounding, and the lesions were collected. Myofibroblast density, macrophage number, catecholamine level, collagen deposition, and blood vessel number were evaluated. In the intact and gonadectomized groups, stress increased the plasma catecholamine levels in both genders. In intact groups, stress impaired wound contraction and re-epithelialization and increased the macrophage number in males but not in females. In addition, stress compromised myofibroblastic differentiation and blood vessel formation and decreased collagen deposition in males but not in females. In contrast to intact mice, wound healing in ovariectomized female mice was affected by stress, while wound healing in castrated male mice was not. In conclusion, gender differences contribute to the cutaneous wound healing of chronically stressed mice. In addition, androgens contribute to the stress-induced impairment of the healing of cutaneous wounds but estrogens inhibit it.
Collapse
Affiliation(s)
- Bruna Romana-Souza
- Department of Animal Biology, Rural Federal University of Rio de Janeiro, Seropédica, Brazil; Department of Histology and Embryology, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
| | | | - Gabriela R Pereira
- Department of Animal Biology, Rural Federal University of Rio de Janeiro, Seropédica, Brazil
| | - Andréa Monte-Alto-Costa
- Department of Histology and Embryology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| |
Collapse
|
|
14
|
Yao X, Wigginton JG, Maass DL, Ma L, Carlson D, Wolf SE, Minei JP, Zang QS. Estrogen-provided cardiac protection following burn trauma is mediated through a reduction in mitochondria-derived DAMPs. Am J Physiol Heart Circ Physiol 2014; 306:H882-94. [PMID: 24464748 DOI: 10.1152/ajpheart.00475.2013] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Mitochondria-derived danger-associated molecular patterns (DAMPs) play important roles in sterile inflammation after acute injuries. This study was designed to test the hypothesis that 17β-estradiol protects the heart via suppressing myocardial mitochondrial DAMPs after burn injury using an animal model. Sprague-Dawley rats were given a third-degree scald burn comprising 40% total body surface area (TBSA). 17β-Estradiol, 0.5 mg/kg, or control vehicle was administered subcutaneously 15 min following burn. The heart was harvested 24 h postburn. Estradiol showed significant inhibition on the productivity of H2O2 and oxidation of lipid molecules in the mitochondria. Estradiol increased mitochondrial antioxidant defense via enhancing the activities and expression of superoxide dismutase (SOD) and glutathione peroxidase (GPx). Estradiol also protected mitochondrial respiratory function and structural integrity. In parallel, estradiol remarkably decreased burn-induced release of mitochondrial cytochrome c and mitochondrial DNA (mtDNA) into cytoplasm. Further, estradiol inhibited myocardial apoptosis, shown by its suppression on DNA laddering and downregulation of caspase 1 and caspase 3. Estradiol's anti-inflammatory effect was demonstrated by reduction in systemic and cardiac cytokines (TNF-α, IL-1β, and IL-6), decrease in NF-κB activation, and attenuation of the expression of inflammasome component ASC in the heart of burned rats. Estradiol-provided cardiac protection was shown by reduction in myocardial injury marker troponin-I, amendment of heart morphology, and improvement of cardiac contractility after burn injury. Together, these data suggest that postburn administration of 17β-estradiol protects the heart via an effective control over the generation of mitochondrial DAMPs (mtROS, cytochrome c, and mtDNA) that incite cardiac apoptosis and inflammation.
Collapse
Affiliation(s)
- Xiao Yao
- Departments of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
| | | | | | | | | | | | | | | |
Collapse
|
|
15
|
Yang LJ, Wan R, Shen JQ, Shen J, Wang XP. Effect of L-cysteine on remote organ injury in rats with severe acute pancreatitis induced by bile-pancreatic duct obstruction. Hepatobiliary Pancreat Dis Int 2013; 12:428-35. [PMID: 23924502 DOI: 10.1016/s1499-3872(13)60067-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Remote organ failure occurs in cases of acute pancreatitis (AP); however, the reports on AP induced by pancreatic duct obstruction are rare. In this study we determined the effect of L-cysteine on pancreaticobiliary inflammation and remote organ damage in rats after pancreaticobiliary duct ligation (PBDL). METHODS AP was induced by PBDL in rats with 5/0 silk. Sixty rats were randomly divided into 4 groups. Groups A and B were sham-operated groups that received injections of saline or L-cysteine (10 mg/kg) intraperitoneally (15 rats in each group). Groups C and D were PBDL groups that received injections of saline or L-cysteine (10 mg/kg) intraperitoneally (15 rats in each group). The tissue samples of the pancreas and remote organs such as the lung, liver, intestine and kidney were subsequently examined for pathological changes under a light microscope. The samples were also stored for the determination of malondialdehyde and glutathione levels. Blood urea nitrogen (BUN), plasma amylase, ALT and AST levels were determined spectrophotometrically using an automated analyzer. Also, we evaluated the effect of L-cysteine on remote organ injury in rats with AP induced by retrograde infusion of 3.5% sodium taurocholate (NaTc) into the bile-pancreatic duct. RESULTS Varying degrees of injury in the pancreas, lung, liver, intestine and kidney were observed in the rats 24 hours after PBDL. The severity of injury to the lung, liver and intestine was attenuated, while injury status was not changed significantly in the pancreas and kidney after L-cysteine treatment. Oxidative stress was also affected by L-cysteine in PBDL-treated rats. The concentration of tissue malondialdehyde decreased in the pancreas and remote organs of PBDL and L-cysteine administrated rats, and the concentration of glutathione increased more significantly than that of the model control group. However, L-cysteine administration reduced the severity of injury in remote organs but not in the pancreas in rats with NaTc-induced AP. CONCLUSION L-cysteine treatment attenuated multiple organ damage at an early stage of AP in rats and modulated the oxidant/antioxidant imbalance.
Collapse
Affiliation(s)
- Li-Juan Yang
- Department of Gastroenterology, and Shanghai Key Laboratory of Pancreatic Diseases, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai 200080, China
| | | | | | | | | |
Collapse
|
|
16
|
Umit UM, Berna T, Handan K, Ipek E, Berrak Y, Can E, Bahadir GM. Role of Melatonin and Luzindole in Rat Mammary Cancer. J INVEST SURG 2012; 25:345-53. [DOI: 10.3109/08941939.2012.665570] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
|
|
17
|
Lin CY, Hsu CC, Lin MT, Chen SH. Flutamide, an androgen receptor antagonist, improves heatstroke outcomes in mice. Eur J Pharmacol 2012; 688:62-7. [PMID: 22609231 DOI: 10.1016/j.ejphar.2012.05.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2011] [Revised: 04/20/2012] [Accepted: 05/04/2012] [Indexed: 10/28/2022]
Abstract
Flutamide has been used as an adjunct for decreasing the mortality from subsequent sepsis. Heatstroke resembles septic shock in many aspects. We hypothesized that heat-induced multiple organ dysfunction syndromes and lethality could be reduced by flutamide therapy. In heatstroke groups, mice were exposed to whole body heating (41.2°C, for 1h) in a controlled-environment chamber. The heat-stressed mice were returned to normal room temperature (24°C) after whole body heating. Mice still alive on day 4 of WBH treatment were considered survivors. Physiological and biochemical parameters were monitored for 2.5h post-WBH. Heatstroke mice were subcutaneously treated with flutamide (12.5-50mg/kg body weight in 0.05 ml) or vehicle solution (0.05 ml/kg body weight) once daily for 3 consecutive days post-WBH. We evaluated the effect of flutamide in heatstroke mice and showed that flutamide significantly (i) attenuated hypothermia, (ii) reduced the number of apoptotic cells in the hypothalamus, the spleen, the liver, and the kidney, (iii) attenuated the plasma index of toxic oxidizing radicals (e.g., nitric oxide metabolites and hydroxyl radicals), (iv) diminished the plasma index of the organ injury index (e.g., lactate dehydrogenase), (v) attenuated plasma systemic inflammation response molecules (e.g., tumor necrosis factor-α and interleukin-6), (vi) reduced the index of infiltration of polymorphonuclear neutrophils in the lung (e.g., myeloperoxidase activity), and (vii) allowed three times the fractional survival compared with vehicle. Thus, flutamide appears to be a novel agent for the treatment of mice with heatstroke or patients in the early stage of heatstroke.
Collapse
Affiliation(s)
- Chian-Yuh Lin
- The Institute of Basic Medical Sciences, National Cheng Kung University School of Medicine, Tainan, Taiwan
| | | | | | | |
Collapse
|
|
18
|
Koh WP, Yuan JM, Wang R, Govindarajan S, Oppenheimer R, Zhang ZQ, Yu MC, Ingles SA. Aromatase (CYP19) promoter gene polymorphism and risk of nonviral hepatitis-related hepatocellular carcinoma. Cancer 2011; 117:3383-92. [PMID: 21319151 DOI: 10.1002/cncr.25939] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2010] [Revised: 11/19/2010] [Accepted: 12/20/2010] [Indexed: 01/06/2023]
Abstract
BACKGROUND Experimental studies suggest that sex hormones may induce or promote the development of hepatocellular carcinoma (HCC). Androgens are converted to estrogens by the CYP19 gene product, aromatase. Hepatic aromatase level and activity have been shown to be markedly elevated in HCC. Aromatase expression in liver tumors is driven by a promoter upstream of CYP19 exon I.6. METHODS First, the authors identified an A/C polymorphism in the exon I.6 promoter of the CYP19 gene. To determine whether allelic variants in the CYP19 I.6 promoter differ in their ability to drive gene expression, we carried out an in vitro reporter gene assay. Then, the authors studied the association between this polymorphism and HCC risk in 2 complementary case-control studies: 1 in high-risk southern Guangxi, China, and another in low-risk US non-Asians of Los Angeles County. RESULTS Transcriptional activity was 60% higher for promoter vectors carrying the rs10459592 C allele compared with those carrying an A allele (P = .007). In both study populations, among subjects negative for at-risk serologic markers of hepatitis B or C, there was a dose-dependent association between number of high activity C allele and risk of HCC (P(trend) = .014). Risk of HCC was significantly higher (odds ratio [OR], 2.25; 95% confidence interval (CI), 1.18-4.31) in subjects homozygous for the C allele compared with those homozygous for the A allele. CONCLUSIONS This study provides epidemiologic evidence for the role of hepatic aromatization of androgen into estrogen in the development of nonviral hepatitis-related HCC.
Collapse
Affiliation(s)
- Woon-Puay Koh
- Department of Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
| | | | | | | | | | | | | | | |
Collapse
|
|
19
|
Rationale for routine and immediate administration of intravenous estrogen for all critically ill and injured patients. Crit Care Med 2010; 38:S620-9. [DOI: 10.1097/ccm.0b013e3181f243a9] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
|
|
20
|
Omurtag GZ, Güranlioğlu FD, Sehirli O, Arbak S, Uslu B, Gedik N, Sener G. Protective effect of aqueous garlic extract against naphthalene-induced oxidative stress in mice. J Pharm Pharmacol 2010; 57:623-30. [PMID: 15901351 DOI: 10.1211/0022357055939] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Abstract
The aim of this study was to investigate the possible protective effects of aqueous garlic extract (AGE) against naphthalene-induced oxidative changes in liver, kidney, lung and brain of mice. Balb/c mice (25–30 g) of either sex were divided into five groups each comprising 10 animals. Mice received for 30 days: 0.9% NaCl, i.p. (control); corn oil, i.p; AGE in a dose of 125 mg kg−1, i.p.; naphthalene in a dose of 100 mg kg−1, i.p. (dissolved in corn oil); and AGE (in a dose of 125 mg kg−1, i.p.) plus naphthalene (in a dose of 100 mg kg−1, i.p.). After decapitation, liver, kidney, lung and brain tissues were excised. Malondialdehyde (MDA) and glutathione (GSH) levels and myeloperoxidase activity (MPO) were determined in the tissues, while oxidant-induced tissue fibrosis was determined by collagen content. Tissues were also examined microscopically. Serum aspartate aminotransferase, alanine aminotransferase levels and blood urea nitrogen and creatinine concentrations were measured for the evaluation of hepatic and renal function, respectively. MDA and GSH levels were also assayed in serum samples. In the naphthalene-treated group, GSH levels decreased significantly, while MDA levels, MPO activity and collagen content increased in the tissues (P< 0.01–0.001), suggesting oxidative organ damage, which was also verified histologically. In the AGE-treated naphthalene group, all of these oxidant responses were reversed significantly (P< 0.05–0.01). Hepatic and renal function test parameters, which increased significantly (P< 0.001) following naphthalene administration, decreased (P< 0.05–0.001) after AGE treatment. The results demonstrate the role of oxidative mechanisms in naphthalene-induced tissue damage. The antioxidant properties of AGE ameliorated oxidative organ injury due to naphthalene toxicity.
Collapse
Affiliation(s)
- Gülden Z Omurtag
- Department of Pharmaceutical Toxicology, School of Pharmacy, Marmara University, Istanbul, Turkey
| | | | | | | | | | | | | |
Collapse
|
|
21
|
Gatson JW, Maass DL, Simpkins JW, Idris AH, Minei JP, Wigginton JG. Estrogen treatment following severe burn injury reduces brain inflammation and apoptotic signaling. J Neuroinflammation 2009; 6:30. [PMID: 19849845 PMCID: PMC2774304 DOI: 10.1186/1742-2094-6-30] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2009] [Accepted: 10/22/2009] [Indexed: 11/22/2022] Open
Abstract
Background Patients with severe burn injury experience a rapid elevation in multiple circulating pro-inflammatory cytokines, with the levels correlating with both injury severity and outcome. Accumulations of these cytokines in animal models have been observed in remote organs, however data are lacking regarding early brain cytokine levels following burn injury, and the effects of estradiol on these levels. Using an experimental animal model, we studied the acute effects of a full-thickness third degree burn on brain levels of TNF-α, IL-1β, and IL-6 and the protective effects of acute estrogen treatment on these levels. Additionally, the acute administration of estrogen on regulation of inflammatory and apoptotic events in the brain following severe burn injury were studied through measuring the levels of phospho-ERK, phospho-Akt, active caspase-3, and PARP cleavage in the placebo and estrogen treated groups. Methods In this study, 149 adult Sprague-Dawley male rats received 3rd degree 40% total body surface area (TBSA) burns. Fifteen minutes following burn injury, the animals received a subcutaneous injection of either placebo (n = 72) or 17 beta-estradiol (n = 72). Brains were harvested at 0.5, 1, 2, 4, 6, 8, 12, 18, and 24 hours after injury from the control (n = 5), placebo (n = 8/time point), and estrogen treated animals (n = 8/time point). The brain cytokine levels were measured using the ELISA method. In addition, we assessed the levels of phosphorylated-ERK, phosphorylated-Akt, active caspase-3, and the levels of cleaved PARP at the 24 hour time-point using Western blot analysis. Results In burned rats, 17 beta-estradiol significantly decreased the levels of brain tissue TNF-α (~25%), IL-1β (~60%), and IL-6 (~90%) when compared to the placebo group. In addition, we determined that in the estrogen-treated rats there was an increase in the levels of phospho-ERK (p < 0.01) and Akt (p < 0.05) at the 24 hour time-point, and that 17 beta-estradiol blocked the activation of caspase-3 (p < 0.01) and subsequent cleavage of PARP (p < 0.05). Conclusion Following severe burn injury, estrogens decrease both brain inflammation and the activation of apoptosis, represented by an increase in the levels of phospho-Akt and inhibition of caspase-3 activation and PARP cleavage. Results from these studies will help further our understanding of how estrogens protect the brain following burn injury, and may provide a novel, safe, and effective clinical treatment to combat remote secondary burn injury in the brain and to preserve cognition.
Collapse
Affiliation(s)
- Joshua W Gatson
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
| | | | | | | | | | | |
Collapse
|
|
22
|
Kasımay Ö, Şener G, Çakır B, Yüksel M, Çetinel Ş, Contuk G, Yeğen BÇ. Estrogen Protects against Oxidative Multiorgan Damage in Rats with Chronic Renal Failure. Ren Fail 2009; 31:711-25. [DOI: 10.3109/08860220903134563] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
|
|
23
|
Vornehm ND, Wang M, Abarbanell A, Herrmann J, Weil B, Tan J, Wang Y, Kelly M, Meldrum DR. Acute postischemic treatment with estrogen receptor-alpha agonist or estrogen receptor-beta agonist improves myocardial recovery. Surgery 2009; 146:145-54. [PMID: 19628068 DOI: 10.1016/j.surg.2009.04.026] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2009] [Accepted: 04/17/2009] [Indexed: 11/24/2022]
Abstract
BACKGROUND After ischemia/reperfusion (I/R) injury, female hearts demonstrate improved functional recovery compared with male, which suggests a protective role for estrogen. Acute postischemic treatment with 17-beta-estradiol (E2) attenuates myocardial dysfunction. However, it is unknown by which estrogen receptor (ER) E2 mediates this acute cardioprotection during I/R. Therefore, we hypothesize that postischemic infusion of the selective ER-alpha agonist (4,4',4''-[4-propyl-(1H)-pyrazole-1,3,5-triyl]tris-phenol [PPT]) or the selective ER-beta agonist (2,3-bis(4-hydroxyphenyl)-propionitrile [DPN]) will improve myocardial function after I/R injury. METHODS Isolated, perfused hearts (Langendorff) from adult male rats were subjected to 25 minutes of ischemia followed by 40 minutes of reperfusion. Hearts (n = 4-6 per group) were randomly infused with either perfusate, PPT or DPN at 1, 10, or 100 nmol/L throughout reperfusion. After I/R, heart tissue was analyzed for tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, vascular endothelial growth factor (VEGF), and lactate dehydrogenase (LDH). RESULTS Postischemic treatment with 10 nmol/L of PPT significantly improved myocardial function. Additionally, 10 or 100 nmol/L of DPN significantly increased myocardial functional recovery after I/R injury, with maximum benefit at the 10 nmol/L dose. A trend toward lower levels of LDH was noted in DPN- and PPT-treated groups after I/R injury. Neither PPT nor DPN affected myocardial production of TNF-alpha or IL-1beta. However, higher levels of myocardial VEGF were noted in the PPT-treated group compared with controls. CONCLUSION Both ER-alpha and ER-beta are involved in mediating E2-induced rapid cardioprotection after I/R injury. Advancing our understanding of both ER subtypes may be useful for the development of novel strategies that may benefit both males and females in response to myocardial ischemia.
Collapse
Affiliation(s)
- Nicholas D Vornehm
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | | | | | | | | | | | | | | | | |
Collapse
|
|
24
|
|
|
25
|
Gammadelta T-cells: potential regulators of the post-burn inflammatory response. Burns 2008; 35:318-26. [PMID: 18951718 DOI: 10.1016/j.burns.2008.08.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2008] [Accepted: 08/12/2008] [Indexed: 02/02/2023]
Abstract
Severe burn induces an immunopathological response that contributes to the development of a systemic inflammatory response (SIRS) and subsequent multiple organ failure. While, multiple immune cells type (T-cells, macrophages, neutrophils) are involved in this response, recent evidence suggests that a unique T-cell subset, gammadelta T-cells are central in the response to injury. While gammadelta T-cells represent only a small percentage of the total T-cell population, they display specific functional characteristics that uniquely position them in the immune/inflammatory axis to influence a number of important aspects of the body's response to burn. This review will focus on the potential regulator role of gammadelta T-cells in immunopathological response following burn and thereby their potential as therapeutic targets for affecting inflammation and healing.
Collapse
|
|
26
|
|
|
27
|
Huang H, He J, Yuan Y, Aoyagi E, Takenaka H, Itagaki T, Sannomiya K, Tamaki K, Harada N, Shono M, Shimizu I, Takayama T. Opposing effects of estradiol and progesterone on the oxidative stress-induced production of chemokine and proinflammatory cytokines in murine peritoneal macrophages. THE JOURNAL OF MEDICAL INVESTIGATION 2008; 55:133-41. [PMID: 18319556 DOI: 10.2152/jmi.55.133] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
In inflammatory and oxidative liver injury, virus proteins and reactive oxygen species are involved in the regulation of proinflammatory cytokine production by macrophages. This study investigated the effects of estradiol (E2) and progesterone on the unstimulated and oxidative stress-stimulated production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, macrophage inflammatory protein (MIP)-2, and macrophage chemotactic protein (MCP)-1 by peritoneal macrophages isolated from male and female mice. E2 inhibited the cytokine production of TNF-alpha, IL-1beta, MIP-2, and MCP-1 by the unstimulated macrophages from males and females, which was then further stimulated by progesterone. The exposure to hydrogen peroxide in the macrophages from both sexes induced the production of cytokine. The hydrogen peroxide-stimulated cytokine production was suppressed by E2 and enhanced by progesterone. The sex hormone effects on the unstimulated and stimulated macrophages were blocked by their receptor antagonists and showed no significant difference between male and female subjects. These findings suggest that E2 may play a favorable role in the course of persistent liver injury, by inhibiting proinflammatory cytokine production, which, in addition, progesterone may counteract the favorable E2 effects through their receptors.
Collapse
Affiliation(s)
- Huiwei Huang
- Department of Digestive and Cardiovascular Medicine, The University of Tokushima Graduate School, Tokushima, Japan
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Işeri SO, Gedik IE, Erzik C, Uslu B, Arbak S, Gedik N, Yeğen BC. Oxytocin ameliorates skin damage and oxidant gastric injury in rats with thermal trauma. Burns 2008; 34:361-9. [PMID: 17826914 DOI: 10.1016/j.burns.2007.03.022] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2006] [Accepted: 03/29/2007] [Indexed: 11/29/2022]
Abstract
Transient splanchnic vasoconstriction following major burns causes oxidative and/or nitrosative damage in gastrointestinal tissues due to ischemia, which is followed by reperfusion injury. Oxytocin (OT), a hypothalamic nonapeptide, possesses antisecretory and antiulcer effects, facilitates wound healing and is involved in immune and inflammatory processes. To assess the possible protective effect of oxytocin (OT) against burn-induced gastric injury, Sprague-Dawley rats (250-300g) were randomly divided into three groups as control (n=8), OT-treated burn (n=8) and saline-treated burn (n=8) groups. Under anesthesia, the shaved dorsal skin of rats was exposed to 90 degrees C water for 10s to induce burn injury covering 30% of total body surface area in a standardized manner. Either oxytocin (5microg/kg) or saline was administered subcutaneously immediately after and at 24h following burn, and the rats were decapitated at 48h. Serum samples were assayed for TNF-alpha, and stomach was taken for the determination of malondialdehyde (MDA), myeloperoxidase (MPO) activity, DNA fragmentation rate (%) and histopathological examination. MDA and MPO were assayed for products of lipid peroxidation and as an index of tissue neutrophil infiltration, respectively. When compared to control group, burn caused significant increases in gastric MDA and MPO activity and increased microscopic damage scores at 48h (p<0.001). Oxytocin treatment reversed the burn-induced elevations in MDA and MPO levels and reduced the gastric damage scores (p<0.001, p<0.01), while TNF-alpha levels, which were increased significantly at 48thh after injury (p<0.001), were abolished with OT treatment (p<0.001). The results of this study suggest that oxytocin may provide a therapeutic benefit in diminishing burn-induced gastric inflammation by depressing tissue neutrophil infiltration and decreasing the release of inflammatory cytokines, but requires further investigation as a potential therapeutic agent in ameliorating the systemic effects of severe burn.
Collapse
Affiliation(s)
- Sevgin Ozlem Işeri
- Marmara University, School of Medicine, Department of Physiology, Haydarpaşa, Istanbul 34668, Turkey
| | | | | | | | | | | | | |
Collapse
|
|
29
|
Gao C, Sun X, Zhang G, Zhang H, Zhao H, Yang Y, Han L, Xu L, Chai W. Hyperoxygenated Solution Preconditioning Attenuates Lung Injury Induced by Intestinal Ischemia Reperfusion in Rabbits. J Surg Res 2008; 146:24-31. [DOI: 10.1016/j.jss.2007.07.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2007] [Revised: 07/02/2007] [Accepted: 07/17/2007] [Indexed: 11/24/2022]
|
|
30
|
Sierra A, Gottfried-Blackmore A, Milner TA, McEwen BS, Bulloch K. Steroid hormone receptor expression and function in microglia. Glia 2008; 56:659-74. [DOI: 10.1002/glia.20644] [Citation(s) in RCA: 290] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
|
|
31
|
Yuan Y, Shimizu I, Shen M, Aoyagi E, Takenaka H, Itagaki T, Urata M, Sannomiya K, Kohno N, Tamaki K, Shono M, Takayama T. Effects of estradiol and progesterone on the proinflammatory cytokine production by mononuclear cells from patients with chronic hepatitis C. World J Gastroenterol 2008; 14:2200-7. [PMID: 18407594 PMCID: PMC2703845 DOI: 10.3748/wjg.14.2200] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of estradiol (E2) and progesterone on the unstimulated and oxidative stress-stimulated production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-8, and macrophage chemotactic protein (MCP)-1 by peripheral blood mononuclear cells (PBMCs) from patients with chronic hepatitis C and healthy controls.
METHODS: The PBMCs were separated from age-matched 72 males and 71 females with and without chronic hepatitis C, who were divided into two groups based on a mean menopausal age of 50 years. Oxidative stress was induced by hydrogen peroxide in the cells incubated in serum-free media. Cytokines in the culture supernatant were measured by an enzyme-linked immunosorbent assay.
RESULTS: The highest levels of the spontaneous production of TNF-α, IL-1β, IL-8, and MCP-1 by the unstimulated PBMCs were in the older male patients with chronic hepatitis C and the lowest levels were in the pre-menopausal female healthy controls. E2 inhibited the cytokine production by the unstimulated PBMCs from the older male and post-menopausal female patients, which was further stimulated by progesterone. The exposure to hydrogen peroxide in the PBMCs from the younger male and pre-menopausal female healthy subjects induced the production of cytokines. The change rates of the hydrogen peroxide-stimulated cytokine production were suppressed by E2 and enhanced by progesterone.
CONCLUSION: These findings suggest that E2 may play a favorable role in the course of persistent liver injury by preventing the accumulation of monocytes-macrophages and by inhibiting proinflammatory cytokine production, whereas progesterone may counteract the favorable E2 effects.
Collapse
|
|
32
|
Bird MD, Karavitis J, Kovacs EJ. Sex differences and estrogen modulation of the cellular immune response after injury. Cell Immunol 2008; 252:57-67. [PMID: 18294625 PMCID: PMC2544631 DOI: 10.1016/j.cellimm.2007.09.007] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2007] [Accepted: 09/01/2007] [Indexed: 11/22/2022]
Abstract
Cell-mediated immunity is extremely important for resolution of infection and for proper healing from injury. However, the cellular immune response is dysregulated following injuries such as burn and hemorrhage. Sex hormones are known to regulate immunity, and a well-documented dichotomy exists in the immune response to injury between the sexes. This disparity is caused by differences in immune cell activation, infiltration, and cytokine production during and after injury. Estrogen and testosterone can positively or negatively regulate the cellular immune response either by aiding in resolution or by compounding the morbidity and mortality. It is apparent that the hormonal dysregulation is dependent not only on the type of injury sustained but also the amount of circulating hormones. Therefore, it may be possible to design sex-specific therapies to improve immunological function and patient outcome.
Collapse
Affiliation(s)
- Melanie D Bird
- Department of Surgery, Loyola University Medical Center, Maywood, IL 60153, USA
| | | | | |
Collapse
|
|
33
|
Genome-wide changes in expression profile of murine endogenous retroviruses (MuERVs) in distant organs after burn injury. BMC Genomics 2007; 8:440. [PMID: 18045489 PMCID: PMC2241634 DOI: 10.1186/1471-2164-8-440] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2007] [Accepted: 11/28/2007] [Indexed: 01/17/2023] Open
Abstract
Background Previous studies have shown that burn-elicited stress signals alter expression of certain murine endogenous retroviruses (MuERVs) in distant organs of mice. These findings suggest that MuERVs may participate in a network of pathophysiologic events during post-burn systemic response. To gain a better understanding of the biological roles of MuERVs in post-burn systemic response, we examined the genome-wide changes in the MuERV expression profiles in distant organs and the biological properties of the putative-burn related MuERVs were characterized. Results Female C57BL/6J mice were subjected to an approximately 18 % total body surface area flame burn and tissues (liver, lung, and kidney) were harvested at 3 hours and 24 hours after injury. The changes in the MuERV expression profiles in these tissues were examined by RT-PCR using a primer set flanking the non-ecotropic MuERV U3 promoter region within the 3' long terminal repeat. There were differential changes in the expression profiles of MuERV U3 regions after injury in all three tissues examined. Subsequently, a total of 31 unique U3 promoter sequences were identified from the tissues of both burn and no burn mice. An analysis of viral tropisms revealed that putative MuERVs harboring these U3 promoter sequences were presumed to be either xenotropic or polytropic. Some putative transcription regulatory elements were present predominantly in U3 promoter sequences isolated from burn and no burn mice, respectively. In addition, in silico mapping using these U3 sequences as a probe against the mouse genome database identified 59 putative MuERVs. The biological properties (coding potentials for retroviral polypeptides, primer binding sites, tropisms, branching ages, recombination events, and neighboring host genes) of each putative MuERV were characterized. In particular, 16 putative MuERVs identified in this study retained intact coding potentials for all three retroviral polypeptides (gag, pol, and env). None of the putative MuERVs identified in this study were mapped to the coding sequences of host genes. Conclusion In this study, we identified and characterized putative MuERVs whose expression might be altered in response to burn-elicited systemic stress signals. Further investigation is needed to understand the role of these MuERVs in post-burn systemic pathogenesis, in particular, via characterization of their interaction with host genes, MuERV gene products, and viral activities.
Collapse
|
|
34
|
Shimizu I, Kohno N, Tamaki K, Shono M, Huang HW, He JH, Yao DF. Female hepatology: Favorable role of estrogen in chronic liver disease with hepatitis B virus infection. World J Gastroenterol 2007; 13:4295-305. [PMID: 17708600 PMCID: PMC4250853 DOI: 10.3748/wjg.v13.i32.4295] [Citation(s) in RCA: 108] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection is the most common cause of hepatic fibrosis and hepatocellular carcinoma (HCC), mainly as a result of chronic necroinflammatory liver disease. A characteristic feature of chronic hepatitis B infection, alcoholic liver disease and nonalcoholic fatty liver disease (NAFLD) is hepatic steatosis. Hepatic steatosis leads to an increase in lipid peroxidation in hepatocytes, which, in turn, activates hepatic stellate cells (HSCs). HSCs are the primary target cells for inflammatory and oxidative stimuli, and these cells produce extracellular matrix components. Chronic hepatitis B appears to progress more rapidly in males than in females, and NAFLD, cirrhosis and HCC are predominately diseases that tend to occur in men and postmenopausal women. Premenopausal women have lower hepatic iron stores and a decreased production of proinflammatory cytokines. Hepatic steatosis has been observed in aromatase-deficient mice, and has been shown to decrease in animals after estradiol treatment. Estradiol is a potent endogenous antioxidant which suppresses hepatic fibrosis in animal models, and attenuates induction of redox sensitive transcription factors, hepatocyte apoptosis and HSC activation by inhibiting a generation of reactive oxygen species in primary cultures. Variant estrogen receptors are expressed to a greater extent in male patients with chronic liver disease than in females. These lines of evidence suggest that the greater progression of hepatic fibrosis and HCC in men and postmenopausal women may be due, at least in part, to lower production of estradiol and a reduced response to the action of estradiol. A better understanding of the basic mechanisms underlying the sex-associated differences in hepatic fibrogenesis and carciogenesis may open up new avenues for the prevention and treatment of chronic liver disease.
Collapse
Affiliation(s)
- Ichiro Shimizu
- Department of Digestive and Cardiovascular Medicine, Institute of Health Biosciences, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
| | | | | | | | | | | | | |
Collapse
|
|
35
|
Abstract
There is still an unresolved paradox with respect to the immunomodulating role of estrogens. On one side, we recognize inhibition of bone resorption and suppression of inflammation in several animal models of chronic inflammatory diseases. On the other hand, we realize the immunosupportive role of estrogens in trauma/sepsis and the proinflammatory effects in some chronic autoimmune diseases in humans. This review examines possible causes for this paradox. This review delineates how the effects of estrogens are dependent on criteria such as: 1) the immune stimulus (foreign antigens or autoantigens) and subsequent antigen-specific immune responses (e.g., T cell inhibited by estrogens vs. activation of B cell); 2) the cell types involved during different phases of the disease; 3) the target organ with its specific microenvironment; 4) timing of 17beta-estradiol administration in relation to the disease course (and the reproductive status of a woman); 5) the concentration of estrogens; 6) the variability in expression of estrogen receptor alpha and beta depending on the microenvironment and the cell type; and 7) intracellular metabolism of estrogens leading to important biologically active metabolites with quite different anti- and proinflammatory function. Also mentioned are systemic supersystems such as the hypothalamic-pituitary-adrenal axis, the sensory nervous system, and the sympathetic nervous system and how they are influenced by estrogens. This review reinforces the concept that estrogens have antiinflammatory but also proinflammatory roles depending on above-mentioned criteria. It also explains that a uniform concept as to the action of estrogens cannot be found for all inflammatory diseases due to the enormous variable responses of immune and repair systems.
Collapse
Affiliation(s)
- Rainer H Straub
- Laboratory of Experimental Rheumatology and Neuroendocrino-Immunology, Division of Rheumatology, Department of Internal Medicine I, University Hospital, 93042 Regensburg, Germany.
| |
Collapse
|
|
36
|
Abstract
Hepatitis C virus infections are recognized as a major causative factor of chronic liver disease. A characteristic feature of chronic hepatitis C, alcoholic liver disease and non-alcoholic fatty liver disease is hepatic steatosis. Hepatic steatosis leads to an increase in lipid peroxidation in hepatocytes, which, in turn, activates hepatic stellate cells (HSCs). HSCs are also thought to be the primary target cells for inflammatory and oxidative stimuli, and to produce extracellular matrix components. Based on available clinical information, chronic hepatitis C appears to progress more rapidly in men than in women, and cirrhosis is predominately a disease of men and postmenopausal women. Estradiol is a potent endogenous antioxidant. Hepatic steatosis was reported to become evident in an aromatase-deficient mouse and was diminished in animals after treatment with estradiol. Our previous studies showed that estradiol suppressed hepatic fibrosis in animal models, and attenuated HSC activation by suppressing the generation of reactive oxygen species in primary cultures. Variant estrogen receptors were found to be expressed to a greater extent in male patients with chronic liver disease than in female subjects. A better understanding of the basic mechanisms underlying the gender-associated differences observed in the progression of chronic liver disease would provide valuable information relative to the search for effective antifibrogenic therapies.
Collapse
Affiliation(s)
- Ichiro Shimizu
- Department of Digestive and Cardiovascular Medicine, Tokushima University Graduate School of Medicine, Tokushima, Japan
| | | |
Collapse
|
|
37
|
Chen SH, Chang FM, Niu KC, Lin MYS, Lin MT. Resuscitation from experimental heatstroke by estrogen therapy. Crit Care Med 2006; 34:1113-8. [PMID: 16484899 DOI: 10.1097/01.ccm.0000205756.04845.15] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE We investigated the effect of estrogen therapy on inflammatory responses, cardiovascular functions, and survival in a rat model of heatstroke. DESIGN Controlled, prospective study. SETTING Hospital medical research laboratory. SUBJECTS Sprague-Dawley rats (280-312 g of body weight, males and females). INTERVENTIONS Four major groups of anesthetized rats were designated for experiments: a) vehicle-treated male rats; b) vehicle- or premarin-treated estrus female rats; c) vehicle- or premarin-treated ovariectomized rats; and d) vehicle- or premarin-treated leuprolide-treated rats. All animals were exposed to heat stress (ambient temperature 43 degrees C for 70 mins) and then allowed to recover at room temperature (24 degrees C). Their survival time (interval between the onset of heatstroke and animal death) and physiologic and biochemical variables were monitored. Vehicle (normal saline 1 mL/kg of body weight, intravenously) or premarin (1 mg/mL/kg of body weight, intravenously) was administered 70 mins after initiation of heat stress. Ovariectomy or leuprolide (100 mug/kg/day, subcutaneously) injection was conducted 4 wks before the start of heat stress experiments. Another group of rats were exposed to 24 degrees C and used as normothermic controls. MEASUREMENTS AND MAIN RESULTS Compared with the estrus female rats, the ovariectomized rats, the leuprolide-treated rats, and male rats all had lower levels of plasma estradiol and lower survival time values. However, after an intravenous dose of premarin, both the plasma estradiol and survival time values were significantly increased. Compared with the normothermic controls, the vehicle-treated male and ovariectomized rats all displayed higher levels of serum tumor necrosis factor-alpha, which could be suppressed by premarin therapy. In contrast, the serum levels of IL-10 in these groups were significantly elevated by premarin during heatstroke. Furthermore, the heatstroke-induced hyperthermia, arterial hypotension, intracranial hypertension, and cerebral hypoperfusion, hypoxia, and ischemia were significantly attenuated by premarin therapy in ovariectomized rats. CONCLUSIONS We successfully demonstrated that estrogen replacement may improve survival during heatstroke by ameliorating inflammatory responses and cardiovascular dysfunction.
Collapse
Affiliation(s)
- Sheng-Hsien Chen
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | | | | | | | | |
Collapse
|
|
38
|
Abstract
Aging in men is associated with a progressive decline in the production of several hormones, including androgens. The extent to which an age-dependent decline in androgen levels lead to health problems or can affect quality of life remains under debate. Clinical results on replacement therapy do not yet provide a definitive clue on the benefit/risk balance. A sexual dimorphism of the immune system is well established, and the differences between female and male immune responses under normal, as well as pathological, conditions are generally attributed to the influence of estrogens, progestins, and androgens. The suppressive effects of male sex hormones on immune functions have been observed in a wide variety of disease processes and appear to be testosterone-mediated. Endogenous testosterone inhibits skin wound healing response in males and is associated with an enhanced inflammatory response. Although there are no known gender-related differences in permeability barrier function in adults, estrogens accelerates--whereas testosterone retards--barrier development in fetal skin, and male fetuses demonstrate slower barrier development than female littermates.
Collapse
Affiliation(s)
- S Fimmel
- Department of Dermatology, Charité Universitaetsmedizin Berlin, Berlin, Germany
| | | |
Collapse
|
|
39
|
Sener G, Arbak S, Kurtaran P, Gedik N, Yeğen BC. Estrogen Protects the Liver and Intestines Against Sepsis-Induced Injury in Rats. J Surg Res 2005; 128:70-8. [PMID: 16115495 DOI: 10.1016/j.jss.2005.02.019] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2004] [Revised: 02/21/2005] [Accepted: 02/21/2005] [Indexed: 10/25/2022]
Abstract
BACKGROUND AND AIM Sepsis is commonly associated with enhanced generation of reactive oxygen metabolites, leading to multiple organ dysfunctions. The aim of this study was to examine the putative protective role of estradiol against sepsis-induced oxidative organ damage. MATERIALS AND METHODS Sepsis was induced by cecal ligation and puncture method in Wistar albino rats. Sham-operated (control) and sepsis groups received saline or estradiol propionate (10 mg/kg) intraperitoneally immediately after the operation and at 12 h. Twenty-four hours after the surgery, rats were decapitated and malondialdehyde, glutathione levels, and myeloperoxidase activity were determined in the liver and ileum, while oxidant-induced tissue fibrosis was determined by collagen contents. Tissues were also examined microscopically. Serum aspartate aminotransferase, alanine aminotransferase levels, and lactate dehydrogenase were measured for the evaluation of liver functions and tissue damage, respectively. Tumor necrosis factor-alpha was also assayed in serum samples. RESULTS In the saline-treated sepsis group, glutathione levels were decreased significantly, while the malondialdehyde levels, myeloperoxidase activity, and collagen content were increased in the tissues (P < 0.01 to P < 0.001), suggesting oxidative organ damage, which was also verified histologically. In the estradiol-treated sepsis group, all of these oxidant responses were reversed significantly (P < 0.05 to P < 0.01). Liver function tests and tumor necrosis factor-alpha levels, which were increased significantly (P < 0.001) following sepsis, were decreased (P < 0.05 to P < 0.001) with estradiol treatment. CONCLUSION The results demonstrate the role of oxidative mechanisms in sepsis-induced tissue damage, and estradiol, by its antioxidant properties, ameliorates oxidative organ injury, implicating that treatment with estrogens might be applicable in clinical situations to ameliorate multiple organ damage induced by sepsis.
Collapse
Affiliation(s)
- Göksel Sener
- Marmara University School of Pharmacy, Department of Pharmacology and School of Medicine, Istanbul, Turkey.
| | | | | | | | | |
Collapse
|
|
40
|
Cevík H, Erkanli G, Ercan F, Işman CA, Yeğen BC. Exposure to continuous darkness ameliorates gastric and colonic inflammation in the rat: both receptor and non-receptor-mediated processes. J Gastroenterol Hepatol 2005; 20:294-303. [PMID: 15683435 DOI: 10.1111/j.1440-1746.2004.03579.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Melatonin is a hormone involved in the transduction of photoperiodic information, and appears to modulate a variety of neural and endocrine functions. The present study was designed to determine the impact of continuous darkness (CD) on acute gastric and colonic inflammation and the involvement of melatonin receptors in the darkness-related alterations in oxidant gut injury. METHODS Rats were housed either in CD or in standardized light/dark (12/12 h) cycles for 15 days before the induction of colitis or gastric ulcer. Luzindole (MT(2) receptor antagonist) was given at a dose of 0.25 mg/kg intraperitoneally 30 min before and 6 and 18 h following the induction of colitis with acetic acid or gastric ulcer with ethanol. Rats were decapitated at 24 h, and the colons and stomachs were removed for macroscopic scoring, histologic assessment and for the determination of tissue malondialdehyde and glutathione levels. RESULTS All inflammation parameters were increased by acetic acid-induced colitis or ethanol-induced gastric ulcer compared with the control group. Our results indicate that the severity of both gastric and colonic injury is reduced by a 2-week exposure to CD prior to the induction of inflammatory event, while luzindole treatment reversed the protective effect of CD on the colonic and gastric injury. However, darkness-related alterations in malondialdehyde and glutathione levels were not altered by luzindole. CONCLUSION Although the CD-induced amelioration of gut injury involves melatonin receptors, the direct antioxidant effects on melatonin appear to be independent of receptor activity.
Collapse
Affiliation(s)
- Hülya Cevík
- Department of Physiology, Marmara University School of Medicine, Haydarpaşa, Istanbul 34668, Turkey
| | | | | | | | | |
Collapse
|
|
41
|
Barlas A, Cevik H, Arbak S, Bangir D, Sener G, Yeğen C, Yeğen BC. Melatonin protects against pancreaticobiliary inflammation and associated remote organ injury in rats: role of neutrophils. J Pineal Res 2004; 37:267-75. [PMID: 15485553 DOI: 10.1111/j.1600-079x.2004.00168.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Although the role of oxidative stress in acute pancreatitis (AP) has been studied in several animal models, little data are available regarding AP induced by pancreatic duct obstruction. We characterized the protective effects of melatonin on pancreaticobiliary inflammation and associated remote organ injury. In Sprague-Dawley rats, either the common pancreaticobiliary duct (PBDL; n = 28) or bile duct (BDL; n = 28) was ligated or a sham operation was applied (n = 14). Either melatonin (10 mg/kg) or vehicle (saline; 1 mL/kg) was administered intraperitoneally (i.p.) immediately before the surgery and twice a day until the rats were decapitated at 6 or 72 h. The pancreas, liver, kidneys and lungs were removed and tissue samples were stored for the determination of malondialdehyde (MDA) and glutathione (GSH) levels and myelopreoxidase activity. The results demonstrate that pathogenesis of acute obstructive pancreatitis involves not only the oxidative damage of the pancreatic and hepatic tissues, as assessed by increased MDA and reduced GSH levels, but the lungs and kidneys are also challenged by oxidant injury. Similarly, hepatic oxidative injury caused by cholestasis was also accompanied by pulmonary, renal and even pancreatic damage. The biochemical findings were also verified histologically. Melatonin, probably because of its free-radical scavenging and antioxidant activity, which involves an inhibitory effect on tissue neutrophil infiltration, protected all the affected tissues.
Collapse
Affiliation(s)
- Afşar Barlas
- Department of General Surgery, Marmara University School of Medicine, Istanbul, Turkey
| | | | | | | | | | | | | |
Collapse
|
|
42
|
Günal O, Oktar BK, Ozçinar E, Sungur M, Arbak S, Yeğen B. Estradiol treatment ameliorates acetic acid-induced gastric and colonic injuries in rats. Inflammation 2004; 27:351-9. [PMID: 14760943 DOI: 10.1023/b:ifla.0000006703.53427.da] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
To evaluate the role of estrogen treatment on the healing of acetic acid-induced gastric or colonic injury, rats were given 17beta estradiol benzoate (0.001, 0.1, and 10 mg/kg) or vehicle for 7 days (following the induction of ulcer) or 4 days (following the induction of colitis) until they were decapitated. Food intake and fecal output were decreased by estradiol treatment but gastric emptying rate was not changed. Estradiol (10 mg/kg) reduced gastric ulcer index and colonic damage score compared to vehicle-treated groups. SEM and light microscopy demonstrated a significant reduction in the severity of ulcers and colitis by estradiol treatment. Gastric microscopic score was not changed by estradiol treatment, whereas in the colonic tissue score was significantly reduced. Elevated gastric MPO levels were reduced in gastric but not in colonic tissues as compared with corresponding vehicle groups. In conclusion, exogenous estradiol treatment at pharmacological doses improves the healing of both gastric and colonic injury induced by acetic acid in rats.
Collapse
Affiliation(s)
- Omer Günal
- Department of General Surgery, Düzce School of Medicine, Abant Izzet Baysal University, Düzce, Istanbul, Turkey
| | | | | | | | | | | |
Collapse
|
|
43
|
Güal O, Bozkurt A, Deniz M, Sungur M, Yeğen BC. Effect of sex steroids on colonic distension-induced delay of gastric emptying in rats. J Gastroenterol Hepatol 2004; 19:975-81. [PMID: 15304112 DOI: 10.1111/j.1440-1746.2004.03409.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIM The objective of the present study was to examine the effect of gonadal hormones on gastric motor response to non-noxious and noxious stimuli of colonic distension. METHODS Male Wistar albino rats were used. Under ketamine anesthesia some rats underwent castration (n = 24), while the rest of the rats were sham-operated (n = 67) and divided into different groups (n = 7-8 per group). On the 15th day of surgery, liquid gastric emptying studies were commenced. RESULTS Non-noxious (P < 0.05) or noxious (P < 0.01) colonic distension inhibited gastric emptying rate. Estradiol pretreatment (20 micro g/kg per day, for 5 days, s.c.) inhibited gastric motility, while estradiol pretreatment or castration of the rats prior to noxious distension prevented the delay in gastric emptying. In contrast, blockade of testosterone receptors had no effect on the delay in gastric emptying induced by either modes of distension. CONCLUSIONS The results suggest that sex steroids have a modulatory role on the feedback control of gastric motility induced by noxious colonic distension.
Collapse
Affiliation(s)
- Omer Güal
- Department of General Surgery, Düzce School of Medicine, Abant Izzet Baysal University, Düzce, Turkey
| | | | | | | | | |
Collapse
|
|
44
|
Toth B, Alexander M, Daniel T, Chaudry IH, Hubbard WJ, Schwacha MG. The role of γδ T cells in the regulation of neutrophil-mediated tissue damage after thermal injury. J Leukoc Biol 2004; 76:545-52. [PMID: 15197233 DOI: 10.1189/jlb.0404219] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Thermal injury induces an inflammatory response that contributes to the development of secondary tissue damage. Neutrophil recruitment and activation are in part responsible for this tissue damage. Although gammadelta T cells have been shown to regulate the inflammatory responses in tissues that are prone to neutrophil-mediated injury post-burn, their role in the induction of secondary tissue injury post-burn remains unknown. To study this, gammadelta T cell-deficient (gammadelta TCR-/-) and wild-type (WT) mice were subjected to thermal injury or sham procedure, and tissue samples were isolated 1-24 h thereafter. Burn injury induced neutrophil accumulation in the lung and small intestines of WT mice at 1-3 h post-injury. No such increase in neutrophil tissue content was observed in gammadelta TCR-/- mice. An increase in tissue wet/dry weight ratios was also observed in these organs at 3 h post-burn in WT but not in gammadelta TCR-/- mice. A parallel increase in plasma and small intestine levels of the chemokines macrophage-inflammatory protein-1beta (chemokine ligand 4) and keratinocyte-derived chemokine (CXC chemokine ligand 1) were observed in injured WT mice but not in injured gammadelta TCR-/- mice. Increased activation (CD120b expression) of the circulating gammadelta T cell population was also observed at 3 h post-burn in WT mice. These results indicate the gammadelta T cells, through the production of chemokines, play a central role in the initiation of neutrophil-mediated tissue damage post-burn.
Collapse
MESH Headings
- Animals
- Antigens, CD/immunology
- Burns/immunology
- Burns/pathology
- Burns/physiopathology
- Cell Division/genetics
- Cell Division/immunology
- Chemokine CCL4
- Chemotaxis, Leukocyte/genetics
- Chemotaxis, Leukocyte/immunology
- Immunologic Deficiency Syndromes/genetics
- Inflammation/immunology
- Inflammation/pathology
- Inflammation/physiopathology
- Intestine, Small/immunology
- Intestine, Small/physiopathology
- Lung/immunology
- Lung/pathology
- Lung/physiopathology
- Macrophage Inflammatory Proteins/immunology
- Macrophage Inflammatory Proteins/metabolism
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Neutrophils/immunology
- Receptors, Antigen, T-Cell, gamma-delta/deficiency
- Receptors, Antigen, T-Cell, gamma-delta/genetics
- Receptors, Antigen, T-Cell, gamma-delta/immunology
- Receptors, Interleukin-8A/immunology
- Receptors, Tumor Necrosis Factor/immunology
- Receptors, Tumor Necrosis Factor, Type II
- T-Lymphocytes/immunology
- Up-Regulation/immunology
Collapse
Affiliation(s)
- Balazs Toth
- Center for Surgical Research, Department of Surgery, G094 Volker Hall, 1670 University Blvd., Birmingham, AL 35294-0019, USA
| | | | | | | | | | | |
Collapse
|
|
45
|
Zaets SB, Berezina TL, Xu DZ, Lu Q, Ricci J, Cohen D, Ananthakrishnan P, Deitch EA, Machiedo GW. Burn-induced red blood cell deformability and shape changes are modulated by sex hormones. Am J Surg 2003; 186:540-6. [PMID: 14599622 DOI: 10.1016/j.amjsurg.2003.07.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
BACKGROUND Burns are known to cause changes in red blood cell (RBC) deformability and resting shape. However, it is unclear whether sex and sex hormones can influence the severity of these alterations. METHODS Red blood cell deformability and shape were examined in proestrus and diestrus female rats, ovariectomized female rats, as well as castrated and non-castrated male rats (6 animals per group) subjected to scald burn. Red blood cell deformability was measured by laser ektacytometry and erythrocyte shape was evaluated by scanning electron microscopy. RESULTS Burn-induced RBC deformability changes (decrease in elongation index) and shape alterations (increase in the percentage of reversibly and irreversibly changed cells) were less severe in proestrus females than in diestrus females or males. Ovariectomized rats demonstrated more severe RBC changes than non-ovariectomized ones. The degree of RBC damage was the same in castrated and non-castrated males. CONCLUSIONS Removal of female sex hormones increases the severity of burn-induced RBC, indicating that female sex hormones protect against burn-induced RBC dysfunction. In contrast, male sex hormones do not appear to modulate burn-induced RBC dysfunction.
Collapse
Affiliation(s)
- Sergey B Zaets
- Department of Surgery, MSB G-507, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07107, USA.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Beagley KW, Gockel CM. Regulation of innate and adaptive immunity by the female sex hormones oestradiol and progesterone. FEMS IMMUNOLOGY AND MEDICAL MICROBIOLOGY 2003; 38:13-22. [PMID: 12900050 DOI: 10.1016/s0928-8244(03)00202-5] [Citation(s) in RCA: 296] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Women mount more vigorous antibody- and cell-mediated immune responses following either infection or vaccination than men. The incidence of most autoimmune diseases is also higher in women than in men; however, during pregnancy many autoimmune diseases go into remission, only to flare again in the early post-partum period. Successful pregnancy requires that the female immune system tolerate the presence of a semi-allogeneic graft for 9 months. Oral contraceptive use can increase susceptibility to certain genital tract infections and sexually transmitted diseases in women. Moreover, treatment of mice and rats with female sex hormones is required to establish animal models of genital tract Chlamydia, Neisseria and Mycoplasma infection. This review describes what is currently known about the effects of the female sex hormones oestradiol and progesterone on innate and adaptive immune responses in order to provide a framework for understanding these sex differences. Data from both human and animal studies will be reviewed.
Collapse
Affiliation(s)
- Kenneth W Beagley
- School of Biomedical Sciences, The University of Newcastle, Royal Newcastle Hospital, Newcastle, NSW 2300, Australia.
| | | |
Collapse
|
|
47
|
Abstract
As of this writing, the most common cause of hepatic fibrosis is chronic hepatitis C virus infection (HCV), the characteristic feature of which is hepatic steatosis. Hepatic steatosis leads to an increase in lipid peroxidation in hepatocytes, which in turn activates hepatic stellate cells (HSCs). HSCs are also thought to be the primary target cells for inflammatory stimuli, and produce extracellular matrix components. Based on available clinical information, chronic hepatitis C appears to progress more rapidly in men than in women, and cirrhosis is predominately a disease of men and postmenopausal women. It should be noted that estradiol (E2) is a potent endogenous antioxidant. A recent study has shown that hepatic steatosis became evident in an aromatase-deficient mouse and was diminished in animals, after treatment with E2. Our studies showed that E2 suppressed hepatic fibrosis in hepatic fibrosis models, inhibited the activation of activator protein 1 and nuclear factor-kappa B in cultured hepatocytes undergoing oxidative stress, and attenuated HSC activation in primary culture. Recently, variant oestrogen receptors (ERs) were found to be expressed to a greater extent in male patients with chronic liver disease than in female subjects. We also demonstrated decreased levels of ERs in postmenopausal women and cirrhotic patients of both genders. The actions of E2 are mediated through ER alpha and beta. HSCs have also been found to possess functional ER beta but not ER alpha. A better understanding the basic mechanisms underlying the gender-associated differences observed in the development of hepatic fibrosis would provide valuable information relative to the search for effective antifibrogenic therapies.
Collapse
Affiliation(s)
- Ichiro Shimizu
- Department of Digestive and Cardiovascular Medicine, Tokushima University School of Medicine, Tokushima, Japan.
| |
Collapse
|
|
48
|
Sener G, Sehirli AO, Satiroglu H, Kaçmaz A, Ayanoglu-Dülger G, Yegen BC. Octreotide improves burn-induced intestinal injury in the rat. Peptides 2003; 24:123-7. [PMID: 12576093 DOI: 10.1016/s0196-9781(02)00284-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The local thermal trauma activates a number of systemic mediator cascades, e.g. a complement activation, cytokine production, resulting in a generalized sequestration and a priming of local and systemic neutrophils and macrophages. We aimed to determine the possible protective effect of octreotide (OCT), a synthetic somatostatin analogue, against burn-induced intestinal tissue damage possibly by inhibiting neutrophil infiltration. Under brief ether anaesthesia, shaved dorsum of the rats was exposed to 90 degrees C bath for 10s to induce burn injury. Rats were decapitated either 3, 24 or 72 h after burn injury. Octreotide (10 microg/kg) or saline was administered subcutaneously (s.c.) immediately after the burn injury. In the 24- and 72-h burn groups, OCT injections were repeated three times daily. In the sham group the same protocol was applied except that the dorsum was dipped in a 25 degrees C water bath for 10 s Malondialdehyde (MDA) and glutathione (GSH) levels and myeloperoxidase (MPO) activity were determined in the intestinal tissue. The results demonstrate that burn injury results in significant neutrophil accumulation, as evidenced by increases in MPO activity. The increase in MDA and the concomitant decrease in GSH levels demonstrate the role of oxidative mechanisms in burn injury. OCT may have some beneficial therapeutic effects by reducing neutrophil-dependent injury and related lipid peroxidation following burn trauma.
Collapse
Affiliation(s)
- Göksel Sener
- Department of Pharmacology, School of Pharmacy, Marmara University, Istanbul, Turkey.
| | | | | | | | | | | |
Collapse
|
|
49
|
Ashcroft GS, Mills SJ. Androgen receptor–mediated inhibition of cutaneous wound healing. J Clin Invest 2002. [DOI: 10.1172/jci0215704] [Citation(s) in RCA: 186] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
|
|
50
|
Ashcroft GS, Mills SJ. Androgen receptor-mediated inhibition of cutaneous wound healing. J Clin Invest 2002; 110:615-24. [PMID: 12208862 PMCID: PMC151108 DOI: 10.1172/jci15704] [Citation(s) in RCA: 89] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Impaired wound healing states in the elderly lead to substantial morbidity, mortality, and a cost to the US Health Services of over $9 billion per annum. In addition to intrinsic aging per se causing delayed healing, studies have suggested marked sex-differences in wound repair. We report that castration of male mice results in a striking acceleration of local cutaneous wound healing, and is associated with a reduced inflammatory response and increased hair growth. Using a hairless mouse model, we have demonstrated that testosterone reduction stimulates the healing response not through hair follicle epithelial/mesenchymal cell proliferation, but directly via effects on wound cell populations. We suggest that endogenous testosterone inhibits the cutaneous wound healing response in males and is associated with an enhanced inflammatory response. The mechanisms underlying the observed effects involve a direct upregulation of proinflammatory cytokine expression by macrophages in response to testosterone. Blockade of androgen action systemically, via receptor antagonism, accelerates healing significantly, suggesting a specific target for future therapeutic intervention in impaired wound healing states in elderly males.
Collapse
Affiliation(s)
- Gillian S Ashcroft
- Cells, Immunology and Development, School of Biological Sciences, University of Manchester, Manchester, United Kingdom.
| | | |
Collapse
|