Estrogen increases protective proteins following trauma and hemorrhage
2006; American Physiological Society; Volume: 290; Issue: 3 Linguagem: Inglês
10.1152/ajpregu.00802.2005
ISSN1522-1490
Autores Tópico(s)Eicosanoids and Hypertension Pharmacology
ResumoINFLAMMATION AND CYTOKINESEstrogen increases protective proteins following trauma and hemorrhageDaniel R. MeldrumDaniel R. MeldrumPublished Online:01 Mar 2006https://doi.org/10.1152/ajpregu.00802.2005MoreSectionsPDF (147 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat in an exquisitely complete series of experiments reported in this issue of American Journal of Physiology–Regulatory, Integrative and Comparative Physiology, Dr. Irshad Chaudry's group has brought us one step closer to understanding the mystery that is estrogen (7). It is not surprising to me that this lab has once again made a leading discovery in trauma-resuscitation science. As the recent recipient of the American Heart Association's Lifetime Achievement Award for Trauma Science, Dr. Chaudry has devoted the past several decades of his research efforts to the pursuit of understanding and preventing trauma-hemorrhage-induced immune dysfunction, a clinical problem that claims hundreds of thousands of human lives per year in this country. For the past 10 years, Dr. Chaudry's lab has focused on better understanding the effects of gender and sex hormones on immune dysfunction following various traumatic conditions (12). The group's progress has been remarkable, and as can be seen by their remarkable article in this issue of the Journal (7), these new findings have brought us very close to harnessing estrogen's protective mechanisms in the treatment of trauma and hemorrhage.We have heard a great deal about the protective role that estrogen may play in cardiovascular disease (4–6, 9, 10), but to learn that it protects cardiac and liver function following trauma-hemorrhage (in otherwise nondiseased hearts) is truly "outside the box." Furthermore, the fact that estradiol does so by increasing other long-appreciated endogenous protective proteins, such as the heat shock proteins that Dr. Chaudry's group demonstrates in this issue of the Journal, is another important link that allows a significant fast-forward for the field. Translating these findings to the clinical arena will be the next important challenge. Defining the appropriate population, as well as refining treatment to avoid untoward hormonal effects, adds complexity to that challenge. In this regard, translating the basic animal studies (where results appear consistent) to the clinical arena (where the results appear inconsistent) will be the focus of the remainder of this discussion.Gender differences have been noted in outcome to acute injuries like myocardial infarction, burns, trauma, and sepsis. Hospital-based clinical studies have shown that women have a higher mortality rate after myocardial infarction compared with men (4). In general, the women in many of these studies were older, had higher risk factors (diabetes, hypertension, and congestive heart failure), more complications, and lower likelihood of receiving treatment (8). Importantly, more men died from myocardial infarction before reaching the hospital and the 28-day mortality for men and women was the same (4). This actually suggests that women are relatively protected in the immediate aftermath of a myocardial infarction but are similar to men at the end of a month.Sepsis and trauma are two other inflammatory conditions associated with gender-dependent outcomes. For mortality in trauma, there is either no gender difference (4) or gender difference in blunt trauma but not in penetrating trauma (4). Studies that have found gender differences are inconsistent. Some studies showed benefit only in women >50 years of age (4), whereas others showed benefit only in women 80 years old, whereas others have found lower mortality rates for women (4). In a study by Schroeder and colleagues (reviewed in reference 4) involving septic patients, women demonstrated lower mortality and higher IL-10 and lower TNF-α levels. Fewer female patients in intensive care units developed sepsis, although, once sepsis developed, the mortality rate was the same for men and women (11). Clinical studies on gender differences in mortality after burns present inconsistent evidence. Some studies showed women or only women ages 30–59 years old to have higher mortality, whereas other studies showed that women have a lower incidence of multiorgan dysfunction and sepsis after burns (4).In contrast to the clinical studies, animal studies have consistently found that females do better. Protective effects of acute administration of estrogen, in an in vivo left anterior descending (LAD) coronary artery ischemia-reperfusion (I/R) model, have been shown in different animals (4). Chronic administration of estrogen provides protection from I/R injury in isolated hearts undergoing global ischemia and in hearts undergoing in vivo LAD obstruction. Estrogen also protected against reperfusion-induced arrhythmias after LAD I/R injury. Ovariectomized females have worse cardiac functional recovery after global I/R, in an isolated heart, than sham ovariectomized females or ovariectomized females with estradiol. After burn injury, females have lower cytokine production and better cardiac function. Trauma-hemorrhage leads to depressed immune function and this depression is more severe in males (3, 12, 13). The immune depression is, in part, caused by testosterone (1, 2), because both castration and receptor blockade attenuated this depression. Estrogen also prevented the immune depression caused by trauma-hemorrhage.Animal studies have consistently shown that females are protected against acute injury while clinical studies appear inconsistent. A possible reason is that in animal studies, the female population is well controlled and only proestrous females are used, whereas clinical studies have a heterogeneous population. Furthermore, the underlying condition of humans is less uniform. Indeed, the few animal studies that used diestrous females showed that diestrous females had functional recovery equivalent to males, but lower than proestrous females. This has been borne out by a few clinical studies that showed cardiac function fluctuates with the hormonal changes of menstrual cycle. Thus it is important to know the hormonal status of females and future clinical studies that take this into account may produce more consistent results.One of the incredibly novel aspects of the present study (7) relates to the rapid signaling and complete processing that must have occurred. In this regard, nuclear transcription and extracellular signaling pathways may be regulated by conventional steroid receptors (SR), such as the alpha and beta estrogen receptors. We now appreciate that SRs may affect signaling by two distinct paths: 1) the nuclear transcription path, whereby activated SRs undergo conformational changes allowing nuclear translocation and bind to steroid response elements (SREs) of target genes; and, 2) the cytoplasmic or cell membrane signaling (mSR) path, whereby the activated SR influences cyoplasmic signaling processes, which then modulate gene transcription by three potential MAPK-mediated mechanisms (Fig. 1). The currently appreciated mSR mechanisms include at least three that may be relevant for the signaling required for the present findings: 1) activated MAPK increases the nuclear transcription activity of SRs by phosphorylating the receptor or a coactivator by a feed-forward mechanism; 2) activated MAPK activates other transcription factors that cooperate with SR on SREs; and 3) mediated transcription of genes without SREs.Indeed, this outstanding study by Dr. Chaudry's group brings us one large step closer to harnessing and understanding estrogen's protection. I highly recommend this article (7) to the readership of the Journal. Fig. 1.Simplified schematic by which nuclear transcription and extracellular signaling pathways may be regulated by conventional steroid receptors (SR), such as the alpha and beta estrogen receptors. SRs may affect signaling by two distinct paths: 1) the nuclear transcription path, whereby activated SRs undergo conformational changes, allowing nuclear translocation, and bind to steroid response elements (SREs) of target genes; and 2) the cytoplasmic or cell membrane signaling (mSR) path, whereby the activated SR influences cyoplasmic signaling processes, which then modulate gene transcription by three potential MAPK-mediated mechanisms. mSR mechanisms as marked by the numbered, blue bullets in the figure: 1) activated MAPK increases the nuclear transcription activity of SRs by phosphorylating the receptor or a coactivator by a feed-forward mechanism; 2) activated MAPK activates other transcription factors (TF) that cooperate with SR on SREs; and 3) mediated transcription of genes without SREs. p-HSP, phospho-heat shock protein.Download figureDownload PowerPointREFERENCES1 Angele MK, Ayala A, Cioffi WG, Bland KI, and Chaudry IH. Testosterone: the culprit for producing splenocyte immune depression after trauma hemorrhage. Am J Physiol Cell Physiol 274: C1530–C1536, 1998.Link | ISI | Google Scholar2 Angele MK, Ayala A, Monfils BA, Cioffi WG, Bland KI, and Chaudry IH. Testosterone and/or low estradiol: normally required but harmful immunologically for males after trauma-hemorrhage. J Trauma 44: 78–85, 1998.Crossref | PubMed | Google Scholar3 Angele MK, Knoferl MW, Schwacha MG, Ayala A, Cioffi WG, Bland KI, and Chaudry IH. Sex steroids regulate pro- and anti-inflammatory cytokine release by macrophages after trauma-hemorrhage. Am J Physiol Cell Physiol 277: C35–C42, 1999.Link | ISI | Google Scholar4 Kher A, Wang M, Tsai BM, Pitcher JM, Greenbaum ES, Nagy RD, Patel KM, Wairiuko GM, Markel TA, and Meldrum DR. Sex differences in the myocardial inflammatory response to acute injury. Shock 23: 1–10, 2005.Crossref | PubMed | ISI | Google Scholar5 Meldrum DR. Tumor necrosis factor in the heart. Am J Physiol Regul Integr Comp Physiol 274: R577–R595, 1998.Link | ISI | Google Scholar6 Mendelsohn ME and Karas RH. Molecular and cellular basis of cardiovascular gender differences. Science 308: 1583–1587, 2005.Crossref | PubMed | ISI | Google Scholar7 Szalay L, Shimizu T, Suzuki T, Yu HP, Choudhry MA, Schwacha MG, Rue Iii LW, Bland KI, and Chaudry IH. Estradiol improves cardiac and hepatic function following trauma-hemorrhage: role of enhanced heat shock protein expression. Am J Physiol Regul Integr Comp Physiol 290: R000–R000, 2006.Google Scholar8 Vaccarino V, Krumholz HM, Berkman LF, and Horwitz RI. Sex differences in mortality after myocardial infarction. Is there evidence for an increased risk for women? Circulation 91: 1861–1871, 1995.Crossref | PubMed | ISI | Google Scholar9 Wang M, Baker L, Tsai BM, Meldrum KK, and Meldrum DR. Sex differences in the myocardial inflammatory response to ischemia-reperfusion injury. Am J Physiol Endocrinol Metab 288: E321–E326, 2005.Link | ISI | Google Scholar10 Wang M, Tsai BM, Kher A, Baker LB, Wairiuko GM, and Meldrum DR. Role of endogenous testosterone in myocardial proinflammatory and proapoptotic signaling after acute ischemia-reperfusion. Am J Physiol Heart Circ Physiol 288: H221–H226, 2005.Link | ISI | Google Scholar11 Wichmann MW, Inthorn D, Andress HJ, and Schildberg FW. Incidence and mortality of severe sepsis in surgical intensive care patients: the influence of patient gender on disease process and outcome. Intensive Care Med 26: 167–172, 2000.Crossref | PubMed | ISI | Google Scholar12 Wichmann MW, Zellweger R, DeMaso CM, Ayala A, and Chaudry IH. Enhanced immune responses in females, as opposed to decreased responses in males following haemorrhagic shock and resuscitation. Cytokine 8: 853–863, 1996.Crossref | PubMed | ISI | Google Scholar13 Zellweger R, Wichmann MW, Ayala A, Stein S, DeMaso CM, and Chaudry IH. Females in proestrus state maintain splenic immune functions and tolerate sepsis better than males. Crit Care Med 25: 106–110, 1997.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: D. R. Meldrum, 545 Barnhill Dr., Emerson Hall Rm. 215, Indianapolis, IN 46202 Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByEstrogen and the female heartMolecular and Cellular Endocrinology, Vol. 389, No. 1-2Age-related differences in cardiac ischemia–reperfusion injury: effects of estrogen deficiency23 March 2013 | Pflügers Archiv - European Journal of Physiology, Vol. 465, No. 5THE ROLE OF ESTROGEN AND RECEPTOR AGONISTS IN MAINTAINING ORGAN FUNCTION AFTER TRAUMA-HEMORRHAGEShock, Vol. 31, No. 3Estradiol's Salutary Effects on Keratinocytes Following Trauma-Hemorrhage Are Mediated by Estrogen Receptor (ER)-α and ER-β1 November 2008 | Molecular Medicine, Vol. 14, No. 11-12PROESTRUS FEMALE RATS ARE MORE RESISTANT TO RIGHT VENTRICULAR PRESSURE OVERLOADShock, Vol. 30, No. 3Flutamide protects against trauma-hemorrhage-induced liver injury via attenuation of the inflammatory response, oxidative stress, and apopotosisWen-Hong Kan, Chi-Hsun Hsieh, Martin G. Schwacha, Mashkoor A. Choudhry, Raghavan Raju, Kirby I. Bland, and Irshad H. Chaudry1 August 2008 | Journal of Applied Physiology, Vol. 105, No. 2Sex Steroids and Stem Cell Function5 May 2008 | Molecular Medicine, Vol. 14, No. 7-8Estrogen, NFκB, and the Heat Shock Response11 April 2008 | Molecular Medicine, Vol. 14, No. 7-8Deleterious effects of endogenous and exogenous testosterone on mesenchymal stem cell VEGF productionRinki Ray, Christine M. Herring, Troy A. Markel, Paul R. Crisostomo, Meijing Wang, Brent Weil, Tim Lahm, and Daniel R. Meldrum1 May 2008 | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. 294, No. 5Estrogen-mediated activation of non-genomic pathway improves macrophages cytokine production following trauma-hemorrhage1 January 2007 | Journal of Cellular Physiology, Vol. 214, No. 3Activation of individual tumor necrosis factor receptors differentially affects stem cell growth factor and cytokine productionTroy A. Markel, Paul R. Crisostomo, Meijing Wang, Christine M. Herring, and Daniel R. Meldrum1 October 2007 | American Journal of Physiology-Gastrointestinal and Liver Physiology, Vol. 293, No. 4Estrogen receptor-α predominantly mediates the salutary effects of 17β-estradiol on splenic macrophages following trauma-hemorrhageTakao Suzuki, Tomoharu Shimizu, Huang-Ping Yu, Ya-Ching Hsieh, Mashkoor A. Choudhry, Kirby I. Bland, and Irshad H. Chaudry1 September 2007 | American Journal of Physiology-Cell Physiology, Vol. 293, No. 3Metabolic modulators following trauma sepsis: Sex hormonesCritical Care Medicine, Vol. 35, No. SupplRole of p38 mitogen-activated protein kinase pathway in estrogen-mediated cardioprotection following trauma-hemorrhageJun-Te Hsu, Ya-Ching Hsieh, Wen Hong Kan, Jian Guo Chen, Mashkoor A. Choudhry, Martin G. Schwacha, Kirby I. Bland, and Irshad H. Chaudry1 June 2007 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 292, No. 6Iron chelation acutely stimulates fetal human intestinal cell production of IL-6 and VEGF while decreasing HGF: the roles of p38, ERK, and JNK MAPK signalingTroy A. Markel, Paul R. Crisostomo, Meijing Wang, Christine M. Herring, Tim Lahm, Kirstan K. Meldrum, Keith D. Lillemoe, Frederick J. Rescorla, and Daniel R. Meldrum1 April 2007 | American Journal of Physiology-Gastrointestinal and Liver Physiology, Vol. 292, No. 4Liver cytokine production and ICAM-1 expression following bone fracture, tissue trauma, and hemorrhage in middle-aged miceTakeshi Matsutani, Shih-Ching Kang, Masao Miyashita, Koji Sasajima, Mashkoor A. Choudhry, Kirby I. Bland, and Irshad H. Chaudry1 January 2007 | American Journal of Physiology-Gastrointestinal and Liver Physiology, Vol. 292, No. 1Tissue compartment-specific role of estrogen receptor subtypes in immune cell cytokine production following trauma-hemorrhageTakao Suzuki, Tomoharu Shimizu, Huang-Ping Yu, Ya-Ching Hsieh, Mashkoor A. Choudhry, Martin G. Schwacha, and Irshad H. Chaudry1 January 2007 | Journal of Applied Physiology, Vol. 102, No. 1Lidocaine depresses splenocyte immune functions following trauma-hemorrhage in miceTakashi Kawasaki, Mashkoor A. Choudhry, Martin G. Schwacha, Kirby I. Bland, and Irshad H. Chaudry1 November 2006 | American Journal of Physiology-Cell Physiology, Vol. 291, No. 5Effects of 17β-estradiol and flutamide on splenic macrophages and splenocytes after trauma-hemorrhageCytokine, Vol. 36, No. 3-4Endocytosis pathways in endothelium: how many?Radu V. Stan1 May 2006 | American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol. 290, No. 5 More from this issue > Volume 290Issue 3March 2006Pages R809-R811 Copyright & PermissionsCopyright © 2006 the American Physiological Societyhttps://doi.org/10.1152/ajpregu.00802.2005PubMed16467507History Published online 1 March 2006 Published in print 1 March 2006 Metrics
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