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Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas 75390
Submitted 22 July 2003 ; accepted in final form 15 September 2003
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, interleukin-1
, and nitric oxide to a lesser extent in proestrus/estrus females than levels secreted by either diestrus females or males. Similarly, myocytes from proestrus/estrus females accumulated significantly less sodium/calcium compared with values measured in males (P < 0.05). Our data confirm gender-related differences in myocardial function and myocardial inflammatory responses to burn injury.
estrous cycle in females; tumor necrosis factor-; interleukin-1; interleukin-6; interleukin-10; nitric oxide secretion by myocytes; primary cardiomyocyte cultures; rat model of burn injury; Langendorff-perfused hearts; myocardial function
Recent studies have suggested that gender is another important determinant of outcome in patients with traumatic injury and sepsis. Although age and the female gender have been associated with a worse prognosis in acute myocardial infarction (28), other studies have described a better survival rate for women with sepsis (15, 34, 38, 39, 46). The mechanisms of gender-related differences in outcome in injury and disease remain unclear, but sexual dimorphism in pro- and anti-inflammatory responses to injury have been implicated. In this regard, Schroeder and colleagues (38) suggested that the significantly improved prognoses for women with sepsis compared with men correlated with significantly lower TNF- bioactivity and increased levels of IL-10 in women compared with levels measured in men. Similarly, Oberholzer and colleagues (34) described higher plasma IL-6 levels in severely injured males compared with levels measured in females with a similar injury severity score (ISS 
25 points) during the early posttrauma period. Balteskard and colleagues (9) described lower thromboxane B2 and TNF- levels in young women compared with young male trauma patients, and differences in inflammatory cytokine profiles were minimized with increasing age, particularly with the onset of menopause. Collectively, these data suggest that gender-related differences in outcome after trauma and sepsis are related to hormonal status.
The role of sex hormones in determining morbidity and mortality after trauma and sepsis has received considerable attention, and several clinical studies have suggested that the rise in circulating estrogen levels and fall in testosterone levels in trauma subjects are evidence of compensatory mechanisms directed to provide protection against trauma-related morbidity/morality (6). Testosterone depletion or blockade (flutamide) has been shown to provide considerable organ protection and to improve outcome in models of injury and sepsis. In this regard, Angele and colleagues (7) showed that testosterone receptor blockade after hemorrhage in male animals ablated immune depression and improved survival after a subsequent septic challenge, whereas Remmers and colleagues (35) described that testosterone receptor blockade with flutamide restored organ blood flow and improved tissue oxygen consumption in male rats subjected to trauma and hemorrhage. The negative effects of a rise in circulating testosterone levels have also been linked to increased thrombanxe A2 receptor density in the aorta (25), inhibition of prostacyclin production by smooth muscle cells (32), and increased vasoconstriction and impaired peripheral perfusion (25, 32). The role of sex hormones in the outcome after trauma and sepsis has been further supported by studies that showed that either estrogen or progesterone administration improved cardiovascular function and altered macrophage cytokine release after trauma hemorrhage (3, 5, 14). Similarly, Altura and colleagues (1–3) showed that estradiol treatment of males subjected to either lethal intestinal ischemia or whole body trauma prevented the reticuloendothelial system phagocytic depression that was shown to occur in untreated males subjected to these injuries; the role of estrogen in peripheral vascular function has been supported by studies from this group showing that treatment of rats with estrogen selectively enhanced vasoconstrictor responses to neurohypohyseal hormones and catecholamines.
Despite a growing body of evidence suggesting gender-related differences in surgical intensive care patients, patients with myocardial infarction, and patients with trauma and sepsis, there is less information describing the effects of gender on organ function and outcome after major burn trauma. Barrow and Herndon (10) described that mortality was significantly higher in male children with severe thermal injury compared with female children with a similar percent total body surface area (TBSA) burn. In contrast, Tobiasen et al. (42) and O'Keefe and colleagues (33) described that the mortality risk was significantly increased in women 30–59 yr of age compared with men of similar age and percent TBSA burn.
Our previous experimental and clinical studies have confirmed burn-related myocardial injury and myocardial contractile dysfunction (8, 17, 37), and we have shown that postburn myocardial abnormalities correlated with myocardial inflammation (23). Therefore, the present study was designed to determine whether gender-related differences in myocardial inflammatory responses after burn injury are associated with sexual dimorphism in the myocardial contractile response to burn injury.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Identification of the estrous cycle. Vaginal smears were performed daily to profile the rat estrous cycle. Each day, between 9:00 and 10:00 AM, vaginal epithelial cells were obtained from each animal using a vaginal flush consisting of tap water. Microscopic examination of the vaginal epithelial cells identified the proestrus state based on the population of nucleated cells; estrous was identified from the markedly swollen, cornified cells that lacked nuclei, whereas diestrus was defined by the numerous leukocytes that appeared in addition to nucleated cells and shrunken cornified cells (20a).
Catheter placement and burn procedure. Rats were anesthetized lightly with isoflurane 12–13 h before the burn experiment, and body hair on the side, back, and neck was closely clipped. The neck region was treated with a surgical scrub, the left carotid artery was exposed, and a polyethylene (PE) catheter (PE-50) inserted into the artery was advanced retrogradely to the level of the aortic arch. In addition, a PE-50 catheter placed in the right external jugular vein was used to administer fluids and drugs. All catheters were filled with heparinized saline, exteriorized, and secured at the nape of the neck. Twelve hours after catheter placement, animals were deeply anesthetized (isoflurane) and secured in a constructed template device, and the surface of the skin exposed through the aperture in the template was immersed in 100°C water for 10 s on the back and upper sides. Use of the template produced a well-circumscribed burned area, avoided injury to the abdominal organs, and accomplished full-thickness dermal burns over 40% TBSA. Exposure to this water temperature in adult rats has been shown previously by our laboratory to destroy all underlying nerves, to produce a transient rise in internal body temperature (<0.5°C for 30–45 s) after exposure to the 100°C water, and to avoid injury to underlying organs. Sham burn rats were subjected to identical preparation except that they were immersed in room temperature water and served as controls. Immediately after immersion, rats were dried and returned to individual cages, and each external jugular catheter was connected to a swivel device (BSP99 Syringe Pump, Braintree Scientific; Braintree, MA) for fluid administration (4 ml/kg per %burn of lactated Ringer solution with one-half of the calculated volume given during the first 8 h postburn and the remaining volume given over the next 16 h postburn). The total volume of Ringer solution given over the first 24 h postburn was 50–56 ml. Buprenorphine (50 µg/kg) was given every 8 h during the postburn period. Burned rats did not display discomfort or pain, moved freely about the cage, and consumed food and water within 20 min after recovering from anesthesia. In the sham burn group, the external jugular vein was cannulated, and lactated Ringer solution was given to maintain catheter patency (0.2 ml·kg–1·h–1). Sham burns also received identical regimens of analgesics (buprenorphine) throughout the study period. Twenty-four hours after burn injury, body temperature was measured with a rectal temperature probe (model 44TA, YSL-Tele Thermometer), and the respiratory rate was monitored by counting respiratory movement. Systemic blood pressure was measured using a Gould-Statham pressure transducer (model IDP23, Gould Instruments; Oxnard, CA) connected to a Grass medical recorder (model 7D Polygraph, Grass Instruments; Quincy, MA). A Grass tachycardiograph (model 7P4F) was used to monitor heart rate. A Grass Poly VIEW Data-Acquisition System was used to convert the acquired data into digital form (45).
Isolated coronary-perfused hearts. To isolate cardiomyocytes, rats received an intraperitoneal injection of heparin (2,000 units) 20–30 min before death. The rats were decapitated, and hearts were harvested and placed in a petri dish containing room temperature heart medium [113 mM NaCl, 4.7 mM KCl, 0.6 mM KH2PO4, 0.6 mM Na2HPO4, 1.2 mM MgSO4, 12 mM NaHCO3, 10 mM KHCO3, 20 mM D-glucose, 0.5x BME amino acids (50x, GIBCO-BRL 11130-051), 10 mM HEPES, 30 mM taurine, 2.0 mM carnitine, and 2.0 mM creatine], which was bubbled constantly with 95% O2-5% CO2. Hearts were cannulated via the aorta and perfused with heart medium at a rate of 12 ml/min for a total of 5 min in a nonrecirculating mode. Enzymatic digestion was initiated by perfusing the heart with digestion solution, which contained 34.5 ml of heart medium as described above plus 50 mg of collagenase II (Lot MOB3771, Worthington 4177), 50 mg BSA (fraction V, GIBCO-BRL 11018-025), 0.5 ml trypsin (2.5%, 10x, GIBCO-BRL 15090-046), 100 mM CaCl2, and 40 mM 2,3-butanedione monoxime (BDM). Enzymatic digestion was accomplished by recirculating this solution through the heart at a flow rate of 12 ml/min for 20 min. All solutions perfusing the heart were maintained at a constant temperature of 37°C. At the end of the enzymatic digestion, the ventricles were removed and mechanically disassociated in 6 ml of enzymatic digestion solution containing a 6-ml aliquot of 2x BDM-BSA solution (3 mg BSA, fraction V, to 150 ml of BDM stock, 40 mM). After mechanical disassociation with fine forceps, the tissue homogenate was filtered through a mesh filter into a conical tube. The cells adhering to the filter were collected by washing with an additional 10-ml aliquot of 1x BDM-BSA solution (prepared by combining 100 ml of BDM stock, 40 mM; 100 ml of heart medium as described above; and 2 g of BSA, fraction V). Cells were then allowed to pellet in the conical tube for 10 min. The supernatant was removed, and the pellet was resuspended in 10 ml of 1x BDM-BSA. The cells were washed and pelleted further in BDM-BSA buffer with increasing increments of calcium (100, 200, and 500 µM to a final concentration of 1,000 µM). After the final pelleting step, the supernatant was removed, and the pellet was resuspended in MEM [prepared by adding 10.8 g of 1x MEM (Sigma M-1018), 11.9 mM NaHCO3, 10 M HEPES, and 10 ml penicillin-streptomycin (100x, GIBCO-BRL 1540-122) with 950 ml MilliQ water]; the total volume was adjusted to 1 liter. At the time of MEM preparation, the medium was bubbled with 95% O2-5% CO2 for 15 min and the pH was adjusted to 7.1 with 1 M NaOH. The solution was then filter sterilized and stored at 4°C until use. At the final concentration of calcium, the cardiomyocyte cell number was calculated and myocyte viability was determined (18).
Cytokine secretion by cardiomyocytes. Myocytes were pipetted into microtiter plates at 5 x 104 cells/microtiter well (12-well cell culture cluster, Corning; Corning, NY) for 18 h (CO2 incubator at 37°C). Supernatants were collected to measure myocyte-secreted TNF-, IL-1, IL-6, IL-10, and nitric oxide (NO) (rat ELISA, Endogen; Woburn, MA). We previously examined the contribution of contaminating cells (nonmyocytes) in our cardiomyocyte preparations using flow cytometry, cell staining (hematoxylin and eosin), and light microscopy. We confirmed that <2% of the total cell number in a myocyte preparation was noncardiomyocytes. Because our preparations are 98% cardiomyocytes, we concluded that the majority of the inflammatory cytokines measured in the cardiomyocyte supernatant was indeed cardiomyocyte derived (18).
Intracellular calcium and sodium measurements. Separate aliquots of cells were loaded with either fura-2 AM for 45 min or sodium-binding benzofurzan isophthalate (SBFI) for 1 h at room temperature in the dark. Myocytes were then suspended in 1.0 mM calcium-containing MEM and washed to remove extracellular dye; myocytes were placed on a glass slide on the stage of a Nikon inverted microscope. The microscope was interfaced with Grooney optics for epi-illumination, a triocular head, phase optics, a x30 phase contrast objective, and a mechanical stage. The excitation illumination source (300-W compact xenon arc illuminator) was equipped with a power supply. In addition, this InCyt Im 2 Fluorescence Imaging System (Intracellular Imaging; Cincinnati, Ohio) included an imaging workstation and Intel Pentium Pro 200-MHz-based personal computer. The computer-controlled filter changer allowed alternation between the 340- and 380-nm excitation wavelengths. Images were captured by a monochrome charge-coupled device camera equipped with a television relay lens. InCyt Im2 Image software allowed measurement of intracellular calcium and sodium concentrations from the ratio of the two fluorescent signals generated from the two excitation wavelengths (340 /380 nm); background was removed by the InCyt IM2 software. The calibration procedure included measurement of the fluorescence ratio with buffers containing different concentrations of either calcium or sodium. At each wavelength, the fluorescence emissions were collected for 1-min intervals, and the time between data collection was 1–2 min. Because quiescent or noncontracting myocytes were used in these studies, the calcium levels measured reflect diastolic levels.
Experimental groups. Adult male rats were randomly divided into two groups: sham burn (group 1) and burn (group 2). Sham burn males were given anesthesia, animal handling, and analgesic administration (group 1) that were identical to procedures described for the burned groups. In group 2, male rats given third-degree scald burn over 40% TBSA received fluid resuscitation and analgesics as described under Catheter placement and burn procedures. Adult female rats were initially divided into proestrus/estrus and diestrus groups based on daily vaginal smears; proestrus/estrus and diestrus groups were then subdivided into sham burn (group 3, proestrus/estrus shams; and group 4, diestrus shams) and burned groups given scald burn injury, fluid resuscitation, and analgesics identical to those described under Catheter Placement and Burn Procedures (group 5, proestrus/estrus burn; and group 6, diestrus burn). Twenty-four hours after burn injury (or sham burn), rats were killed and the hearts were harvested to examine left ventricular (LV) function (Langendorff, n = 7–8 rats/group) or to prepare cardiomyocytes (n = 5–7 rats/group) to examine myocyte inflammatory responses to burn injury.
Statistical analysis. All values are expressed as means ± SE. ANOVA was used to assess the overall difference among the groups for each of the variables. Levene's test for equality of variance was used to suggest the multiple-comparison procedure to be used. If equality of variance among the groups was suggested, multiple-comparison procedures were performed (Bonferroni); if inequality of variance was suggested by Levene's test, Tamhane multiple comparisons (which do not assume equal variance in each group) were performed. Probability values <0.05 were considered statistically significant (analysis was performed using SPSS for Windows, version 7.5.1).
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Hemodynamic-metabolic responses to burn injury. Compared with values measured in time-matched shams, mean arterial blood pressure was significantly lower 24 h after burn injury regardless of gender and despite aggressive fluid resuscitation (Table 1). Hematocrit and serum-ionized calcium levels were significantly lower 24 h after burn injury compared- with values measured in time-matched sham burns. Metabolic acidosis occurred after burn injury in all animals as indicated by the rise in whole blood lactate and the change in base excess (Fig. 1). Arterial lactate levels measured 24 h postburn were significantly lower (P < 0.05) in both groups of burned females compared with values measured in burned males. Serum cytokines measured 24 h after burn injury (or sham burn) are summarized in Fig. 2. These data confirm that all experimental animals responded to burn injury with a significant rise in serum TNF-, IL-1, IL-6 and IL-10 levels; however, these responses were significantly less in burned females than those shown to occur in burned males (P < 0.05).
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Myocardial contractile function. Hearts harvested 24 h after burn injury were perfused (Langendorff) to examine in vitro ventricular performance; Table 2 summarizes the cardiodynamic data collected after a 30-min stabilization period where hearts were perfused at a constant end-diastolic volume, constant heart rate, and constant coronary flow rate. These values were generated before implementation of incremental increases in LV volume to examine Starling relationships and before inotropic challenge (increases in perfusate Ca2+). There were no significant differences in cardiodynamic variables measured in the sham burn groups regardless of gender or regardless of the time of the estrous cycle. Burn trauma produced significant myocardial contractile defects as indicated by a significantly lower LV developed pressure (LVP) and positive and negative maximum first derivative of LVP (±dP/dtmax) compared with values measured in the respective sham burn group. In addition, burn injury in males produced LVP and ±dP/dtmax values that were significantly lower (P < 0.05) than values measured in burned females (P < 0.05) despite an identical percent body surface area burn in all animals (Table 2).
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Myocardial contraction and relaxation deficits in burned males were greater as indicated by the downward and right-ward shift of LV function curves (LVP and ±dP/dt responses to incremental increases in LV volume or preload) compared with function curves calculated for all other experimental groups (Fig. 3A). While burn injury produced cardiac contractile defects in both proestrus/estrus and diestrus females, contraction and relaxation deficits were significantly less in females compared with those measured in burned males (P < 0.05, ANOVA and Student-Neuman-Keuls test), despite an identical burn injury and an identical regimen of fluid resuscitation.
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Figure 3B shows the ventricular responsiveness to increases in perfusate calcium in all experimental groups; all burned animals retained the ability to respond to incremental increases in perfusate calcium with increases in LVP and ±dP/dtmax. However, myocardial contraction and relaxation defects were obvious in all burn groups as indicated by the lower LVP and ±dP/dt values in burns compared with values generated by the respective sham burn groups. In addition, burn-related myocardial contractile defects were significantly (P < 0.05) greater in male burns compared with those documented in burned proestrus/estrus or burned diestrus females despite an identical degree of burn trauma and an identical regimen of fluid resuscitation in all burn groups (ANOVA and Student-Neuman-Keuls test).
We also considered that gender-related alterations in LV compliance may have contributed to the differences in LVP and ±dP/dt responses observed in males compared with diestrus and proestrus/estrus female burns. However, as shown in Fig. 4, LV compliance was similar in sham burn rats; similarly, there were no gender-related differences in LV compliance after burn injury.
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Cardiomyocyte cytokine responses to burn injury. To determine whether gender-related differences in myocardial function correlated with postburn myocardial inflammation and cardiomyocyte secretion of cytokines, additional groups of hearts were prepared from each of the experimental groups and perfused with collagenase-containing buffer, and cardiomyocytes were isolated. As shown in Fig. 5, burn injury promoted TNF-, IL-1, and NO as well as IL-6 and IL-10 secretion by cardiomyocytes, regardless of gender. However, myocytes prepared from male burns secreted significantly greater levels of pro-/anti-inflammatory cytokines than levels measured in cardiomyocytes prepared from proestrus/estrus burns. In contrast, cardiomyocyte cytokine responses to burn injury in diestrus females closely mimicked those seen in burned males.
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To determine whether a previous burn injury altered myocyte cytokine responsiveness to a second insult, additional in vitro studies examined TNF- responses to lipopolysaccharide (LPS) challenge (either 0, 10, or 25 mg LPS per 5 x 104 cardiomyocytes; Fig. 6). All cardiomyocytes prepared from either sham or burn animals responded to LPS challenge with a dose-dependent increase in TNF- secretion. However, TNF- secretion by myocytes prepared from burned animals was significantly greater than cytokine levels secreted by cardiomyocytes prepared from the respective sham groups (P < 0.05). In addition, cardiomyocytes prepared from adult male burns secreted significantly greater levels of TNF- compared with cytokine levels secreted by myocytes prepared from proestrus/estrus females, whereas myocytes prepared from diestrus female burns had TNF- responses to LPS challenge that closely resembled those documented in male burns.
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Cardiomyocyte cation responses to burn injury. Cardiomyocytes prepared from sham burn groups had similar intracellular sodium and calcium levels, regardless of gender. Burn injury produced significant myocyte sodium and calcium accumulation compared with sodium/calcium levels measured in cardiomyocytes prepared from the respective sham burn groups (P < 0.05; Fig. 7). However, myocytes prepared from male burns accumulated significantly greater calcium levels (Fig. 7, top) and greater sodium levels (Fig. 7, bottom) compared with sodium and calcium measured in cardiomyocytes prepared from proestrus/estrus female burns, confirming a gender-related difference in sodium and calcium handling by cardiomyocytes.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Our finding that diestrus female burns had myocardial cytokine profiles resembling those documented in male burns is consistent with a previous report showing that the improved outcome in female trauma and septic patients appeared to be age related, and this improved outcome was lost with the onset of menopause. In this regard, McLauchlan and colleagues (27) showed that mortality was higher in female patients with abdominal sepsis and a mean age of 66 yr compared with males patients of a comparable age range and comparable sepsis. Similarly, Watanakunakorn (44) described that the female gender was associated with a higher mortality rate in a group of patients age 60 yr or older who were diagnosed with Staphylococcus aureus endocarditis. Our finding that myocardial cytokine responses to burn injury were significantly different in proestrus/estrus and diestrus females is also consistent with a report by Krzych et al. (21), who described altered immune responses in different phases of the estrous cycle, and a report by Cannon and Dinarello (13), who described that plasma IL-1 activity was increased in women after ovulation.
We also considered that the greater myocyte inflammatory cytokine secretion in male rats was related to endotoxin contamination of the collagenase used to digest hearts and to prepare myocytes; alternatively, we considered that myocytes from diestrus females and male rats are more sensitive to minuscule amounts of LPS, which may have contaminated our collagenase preparation. In the present study, the collagenase used to digest cardiomyocytes was tested and shown to be endotoxin free. However, our data showed that a second challenge of cardiomyocytes (prepared from all experimental groups) with LPS confirmed a greater sensitivity to LPS challenge in cardiomyocytes prepared from either diestrus females or males as indicated by the higher TNF- levels secreted by cardiomyocytes from these groups and compared with TNF- levels secreted by myocytes prepared from proestrus/estrus females challenged with an identical dose of LPS (25 µg LPS for 18 h). In contrast, loser dose LPS challenge (10 µg for 18 h) produced nearly identical levels of TNF- secretion by myocytes regardless of gender or hormonal status.
Our finding that proestrus/estrus females had less myocardial contractile dysfunction compared with function measured in diestrus females is consistent with previous reports showing that hormonal status plays a significant role in injury and disease (4, 6, 7, 24, 34, 35, 46, 47). That estrogen modulates numerous injury- and disease-related responses has been supported by the finding that administration of low levels of estrogen in males improved peripheral vasoconstrictor responses to catecholamines (1, 2) and improved immune function and outcome in models of trauma-hemorrhage or polymicrobial sepsis. Similarly, administration of testosterone receptor blockade or castration have been associated with improved organ blood flow, improved tissue oxygen consumption, and improved cardiac and hepatic function in males subjected to trauma-hemorrhage (35).
In the present study, burn-related myocardial inflammation, indicated by the increased cardiomyocyte secretion of TNF-, IL-1, IL-6, and NO, is consistent with numerous reports describing cardiomyocyte secretion of inflammatory cytokines in response to a variety of insults including burn trauma, ischemia-reperfusion, and sepsis (18, 19, 23, 45). The role of inflammation in myocardial dysfunction has been further supported by the finding that patients with heart failure have increased circulating levels of IL-1 and TNF-, and the extent to which concentrations of these inflammatory mediators were elevated correlated with greater myocardial dysfunction (22, 43). An additional observation linking myocardial inflammation with myocardial contractile abnormalities is the finding that acute infection and inflammatory disease precipitate transient heart failure (40), as well as the finding that the addition of TNF- to LV muscle preparations or to cardiomyocyte cultures produce contractile defects as well as cardiac myocyte apoptosis (19). In addition, transgenic mice overexpressing TNF- exclusively in the myocardium have myocardial TNF- levels sufficient to cause dilated cardiomyopathy and severe congestive heart failure (12). Finally, anti-TNF strategies have been shown to provide significant cardioprotection in injury models such as burn and sepsis (16, 19). However, in the present study, it was surprising that ventricular function in diestrus burned females was significantly better than function measured in males despite the fact that proinflammatory cytokine profiles in diestrus female burns closely resembled those of male burns. The disparity between cardiomyocyte secretion of inflammatory cytokines and ventricular dysfunction in diestrus female burns suggests that burn-related myocardial abnormalities are not related solely to myocardial proinflammatory cytokine responses to burn injury, and other mediators play a role. In this regard, we considered that gender-related differences in cardiomyocyte sodium/calcium homeostasis may have played a role in cardiac performance, and measures of cardiomyocyte sodium/calcium accumulation provide another index of cardiomyocyte integrity and cellular function. However, burn injury promoted significantly greater myocyte calcium/sodium accumulation in males compared with values measured in female burns, and there were no differences in sodium/calcium levels in diestrus compared with proestrus females.
In the present study, myocardial inflammation and function were examined 24 h after burn injury; this time was selected based on our previous time-course studies confirming that myocardial inflammatory cytokine responses are maximal and myocardial dysfunction reaches a nadir at this time (23). Although we did not examine mortality in this present study, we have shown that mortality over 8 days after burn injury over 40% TBSA in male rats was <10% if fluid resuscitation was based on clinical formulas (4 ml/kg per %burn).
In summary, male rats as well as diestrus and proestrus/estrus females were given a third-degree scald burn over 40% TBSA and fluid resuscitated by a standard clinical protocol. LVP and ±dP/dt responses to increases in preload were significantly lower in burn males compared with responses measured in burn proestrus/estrus females. Burn diestrus females had measures of contraction and relaxation that were significantly better than those measured in burn males but were less than those measured in burn proestrus/estrus females. Similarly, myocytes from proestrus/estrus females secreted significantly less proinflammatory and anti-inflammatory cytokines and accumulated significantly less sodium and calcium compared with values measured in males. Our data confirmed gender-related differences in myocardial function and myocardial inflammatory responses to burn injury.
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ACKNOWLEDGMENTS |
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This study was supported by National Institute of General Medical Sciences Grant 2 P50 GM-21681-38.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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