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Published online before print August 8, 2006
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* Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham Alabama; and
Department of Orthopedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
2 Correspondence: Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, GO94 Volker Hall, 1670 University Boulevard, Birmingham, AL 35294-0019. E-mail: Irshad.Chaudry{at}ccc.uab.edu
ABSTRACT
We hypothesized that administration of androgen receptors antagonist flutamide following trauma-hemorrhage (T-H) in metestrus females will maintain immune function and reduce remote organ damage under those conditions. Female B57BL/J6 mice (metestrus state, 8–12 weeks old) underwent laparotomy and hemorrhagic shock (35.0±5.0 mmHg for 90 min) and then received 17ß-estradiol (E2; 50 µg/25 g), flutamide (625 µg/25 g), or E2 + flutamide. Four hours after resuscitation, plasma cytokine and chemokine (TNF-
, IL-6, IL-10, IFN-
, and MCP-1) concentrations and their release in vitro by hepatic and pulmonary tissue macrophages (M
) were determined by flow cytometry. Organ damage was assessed by edema formation (wet-to-dry weight ratio) and neutrophil infiltration [myeloperoxidase (MPO) activity]. Administration of E2, flutamide, or E2 + flutamide following T-H resulted in a significant decrease in systemic TNF-, IL-6, and MCP-1 concentrations under those conditions. This was accompanied by significantly decreased in vitro TNF- release by Kupffer cells after administration of E2, flutamide, or E2 + flutamide. The in vitro release of proinflammatory cytokines by alveolar M, however, was reduced significantly only by the addition of E2 or E2 + flutamide but not by the addition of flutamide. A significant decrease in pulmonary and hepatic edema formation as well as neutrophil infiltration in the lung was observed after E2, flutamide and E2 + flutamide administration. In contrast, hepatic neutrophil infiltration was only significantly reduced following E2 and E2 + flutamide administration. Thus, although flutamide does not produce synergistic, salutary effects with E2, its administration in females following T-H also produces salutary effects on the immune and organ function, similar to E2 administration under those conditions.
Key Words: cytokines • liver • lungs • neutrophil infiltration • edema
INTRODUCTION
Despite significant improvements in the management of multiple trauma patients, post-traumatic sepsis and multiple organ dysfunction syndrome remain the leading causes of death after trauma. An overwhelming systemic inflammation [systemic inflammatory response syndrome (SIRS)] and post-traumatic immunosuppression have been shown to be involved in the development of these post-traumatic complications [1 2 3 4 5 6 7 8 9 ].
Macrophages (M) play an important role in regulating the immune response following trauma and low flow conditions. Prolonged activation of M, in combination with other leukocytes and endothelial cells, contributes significantly to the development of SIRS and immune dysfunction following trauma and sepsis [10
11
12
]. Thus, information about the functions of M and particularly, the early release of mediators should permit the use of immunomodulatory intervention aimed at ameliorating the hyperinflammatory phase, which may lead to the prevention of remote organ damage and mortality following trauma.
The maladaptive changes of immune cell function have been shown to be influenced significantly by gonadal steroids (e.g., androgen and estrogen) [13 , 14 ]. Females in the proestrus stage of estrus cycle were shown to maintain the immune cell function after trauma-hemorrhage (T-H) [15 , 16 ]. Similarly, administration of 17ß-estradiol (E2) in ovariectomized female or male animals after T-H was also shown to restore immunocompetence in these animals [15 , 16 ].
In contrast to estradiol, testosterone was found to produce deleterious effects on immune cells following T-H [17
, 18
]. In this regard, depletion of testosterone levels by castration prior to T-H prevented the depression in immune functions [17
]. Furthermore, administration of the androgen receptor antagonist flutamide following T-H was shown to maintain immune function in males under those conditions [19
20
21
]. Additional findings showed that treatment of male animals with flutamide markedly increased plasma estrogen levels and estrogen receptor- (ER-) as well as -ß expression on T-lymphocytes and cardiomyocytes [18
, 22
, 23
]. These findings suggest that in addition to blockade of androgen receptors, other flutamide-mediated effects on the hormonal milieu may contribute to the maintenance of immune function after T-H in males. Therefore, the present study examined whether administration of flutamide alone or in combination with E2 in metestrus-cycle (the cycle in which the estrogen levels are the lowest) females following T-H influences the release of M cytokines and whether such alteration in M cytokines affects remote organ damage under those conditions. To determine this, mice were treated with flutamide alone or in combination with E2, and the effects of such treatment on systemic cytokine concentrations and the in vitro cytokine release capacity of hepatic and pulmonary M as well as on the liver and lung tissue damage following T-H were examined.
MATERIALS AND METHODS
Animals and experimental groups
All animal studies were carried out in accordance with the guidelines of the National Institutes of Health (NIH; Bethesda, MD) and were approved by the Institutional Animal Care and Use Committee (University of Alabama at Birmingham).
Female C57/BL6 mice (metestrus, 8–12 weeks old and weighing 19–23 g) were obtained from Charles River Laboratories (Wilmington, MA). The stage of the female reproductive cycle was determined by regular examination of the vaginal smears by the same examiner. The cycle phase was determined from the cytology of vaginal smears obtained daily between 7 and 8 AM. The hemorrhage procedure was started between 9 and 10 AM. Although estrogen levels were not measured in this study, our previous studies have shown that the estrogen concentrations were uniformly low in all animals in the metestrus stage [13 , 15 , 16 ].
E2 and flutamide
A s.c. administration of the vehicle (DMSO) was performed after completion of the sham operation. As our previous studies have shown that administration of E2 or flutamide did not affect the wet-to-dry weight ratio, myeloperoxidase (MPO) ratio, and cytokine release by tissue M in sham-operated animals [17
, 19
], we did not examine a sham group treated with flutamide or E2 in this study. In the T-H groups, E2 (50 µg/25 g), flutamide (625 µg/25 g), the combination of E2 and flutamide (E2, 50 µg/25 g; flutamide, 625 µg/25 g), or vehicle (DMSO) was injected s.c. immediately before the onset of fluid resuscitation.
T-H procedure
Mice in the T-H groups were anesthetized with isoflurane (Minrad, Bethlehem, PA) and restrained in a supine position [13
]. A midline laparotomy was performed, which was closed in two layers with sutures (Ethilon 6/0, Ethicon, Somerville, NJ). Femoral arteries and the right femoral vein were then cannulated with polyethylene tubing (Becton Dickinson, Sparks, MD). Blood pressure was measured via one of the arterial lines using a blood pressure analyzer (Micro-Med, Louisville, KY). Within 10 min after awakening, the animals were bled through the other arterial catheter to a mean arterial blood pressure of 35.0 ± 5.0 mmHg, which was maintained for 90 min. At the end of the procedure, the animals were resuscitated through the venous line with 4x the shed blood volume using Ringer’s lactate. Following resuscitation, the catheters were removed, and the incisions were closed. Sham-operated animals underwent the same surgical procedures but were neither hemorrhaged nor resuscitated.
Harvesting procedures
The animals were re-anesthetized with isoflurane and were killed 4 h following sham operation or the completion of resuscitation in the T-H groups. Blood was obtained via cardiac puncture using a syringe coated with EDTA (Sigma Chemical Co., St. Louis, MO) and centrifuged (10,000 rpm, 10 min, 4°C), and plasma was stored at –80°C for further analysis later. Moreover, lung and liver were removed aseptically.
Determination of wet-dry weight ratios
Wet-to-dry weight ratios of lung (1/2 right lung) and liver (right lobe) were used as a measure of tissue edema [24
]. Tissue samples were weighed immediately after removal (wet weight) and then subjected to desiccation in an oven at 95°C (Blue M®, Asheville, NC) until a stable dry weight was achieved after 48 h. The ratio of the wet-to-dry weight was then calculated.
MPO assay
The accumulation of neutrophils in lung and liver tissue was assessed by determination of the MPO activity [24
]. Tissue samples (1/2 right lung and right liver lobe) were collected, frozen in liquid nitrogen, and stored at –80°C until further assayed. For further analysis, frozen tissue samples were thawed and suspended in 10% phosphate buffer (pH 6.0) containing 1% hexadecyl-trimethylammonium bromide (Sigma Chemical Co.). The samples were sonicated on ice (Sonic Dismembrator, Fisher Scientific, Hampton, NH). The samples were then centrifuged at 12,000 g for 15 min at 4°C, and an aliquot (30 µl) was divided into 180 µl phosphate buffer (pH 6.0) containing 0.167 mg/ml o-dianisidine dihydrochloride and 0.0005% hydrogen peroxide (Sigma Chemical Co.). The change in absorbance at 460 nm was measured spectrophotometrically for 10 min. MPO activity was calculated using a standard curve, which was generated using human MPO (Sigma Chemical Co.). Protein concentrations of the samples were determined using a Bradford assay (Bio-Rad, Hercules, CA).
Alveolar M (AM)
Left lungs were flushed with 1 ml PBS containing 10 IU heparin, three times [25
]. After centrifugation for 15 min at 300 g at 4°C, cells were resuspended in RPMI 1640 (Gibco, Grand Island, NY) containing 10% heat-inactivated FBS and antibiotics (50 U/ml penicillin, 50 µg/ml streptomycin, and 20 µg/ml gentamicin, all from Gibco) to a final concentration of 1 x 105 cells/ml. No significant differences were found between sham animals and vehicle-, E2-, or Flu-treated animals. The suspension was then plated in a 96-well plate, and after 2 h of incubation (37°C, 95% humidity, and 5% CO2), nonadherent cells were removed by washing with PBS (Gibco). Previous studies demonstrated that adherence yielded >95% viable, adhered AM [25
], which in complete RPMI-1640 medium, were stimulated with 10 µg LPS (from Escherichia coli, 055:B5, Sigma Chemical Co.) for 24 h at 37°C, 95% humidity, and 5% CO2. At the end of the incubation period, the supernatants were removed and stored at –80°C until analysis was performed.
Isolation of Kupffer cells (KC)
KC were isolated as described previously [26
]. Briefly, the portal vein was catheterized with a 27-gauge needle, and the liver was perfused with 20 ml HBSS (Gibco) at 37°C, which was followed immediately by perfusion with 15 ml 0.05% collagenase IV (Sigma Chemical Co.) in HBSS with 0.5 mM CaCl2 (Sigma Chemical Co.), also at 37°C. The liver was then removed and transferred to a Petri dish containing the above-mentioned collagenase IV solution. The liver was minced, incubated for 15 min at 37°C, and passed through a sterile, 150-mesh, stainless-steel screen into a beaker containing 10 ml cold HBSS with 10% FBS. The hepatocytes were removed by centrifugation at 50 g for 3 min. The residual cell suspension was washed twice by centrifugation at 800 g for 10 min at 4°C in HBSS. The cells were resuspended in Williams’ E medium containing 10% FBS and antibiotics (50 U/ml penicillin, 50 µg/ml streptomycin, and 20 µg/ml gentamicin, all from Gibco), layered over 16% metrizamide (Accurate Chemical, Westbury, NY) in HBSS, and centrifuged at 2300 g for 45 min at 4°C. After removing the nonparenchymal cells from the interface, the cells were washed twice by centrifugation (800 g, 10 min, 4°C) in Williams’ E medium. The cells were then resuspended in complete Williams’ E medium and plated in a 96-well plate at a density of 5 x 105 cells/ml. No significant differences were found between sham animals and vehicle-, E2-, or Flu-treated animals. After 2 h of incubation (37°C, 95% humidity, and 5% CO2), nonadherent cells were removed by washing with Williams’ E medium. Previous studies demonstrated that adherence yielded >95% viable, adhered KC [13
]. The cells were then cultured under the above-mentioned conditions for 24 h with 10 µg LPS (from E. coli, 055:B5, Sigma Chemical Co.). The cell-free supernatants were harvested and stored at –80°C until assayed.
Flow cytometry
Cytokine concentrations (TNF-, IL-6, IL-10) in plasma and cell-free supernatants were determined with cytokine bead array inflammatory kits using flow cytometry according to the manufacturer’s instructions (BD PharMingen, San Diego, CA).
Statistics
Statistical analysis was performed using Sigma-Stat computer software (SPSS, Chicago, IL). Statistical significance was assumed, where probability values of less than 0.05 were obtained. Comparisons between groups were performed using one-way ANOVAs followed by the Student’s t-test or the rank-sum test (Mann-Whitney U-test). Results are expressed as mean ± SEM.
RESULTS
Wet-to-dry weight ratio
In vehicle-treated animals, T-H resulted in a significantly higher lung (Fig. 1A
) and liver (Fig. 1B)
wet-to-dry weight ratio (edema) compared with sham animals. Administration of E2, flutamide, and the combination of E2 and flutamide following T-H led to a significant reduction of edema formation compared with the vehicle-treated T-H group (P<0.05).
|
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, IL-6, IL-10, and MCP-1 levels compared with the respective sham groups. Administration of E2 and E2 plus flutamide following T-H produces a significant decrease in plasma TNF-, IL-6, IL-10, and MCP-1 concentrations compared with T-H mice treated with vehicle (P<0.05; Fig. 3A
3B
3C
3D
). Flutamide administration also led to a significant decrease in plasma TNF-, IL-6, and MCP-1 levels (P<0.05), whereas plasma IL-10 concentrations were not reduced significantly compared with the vehicle-treated group. Furthermore, plasma IL-6 concentrations were significantly lower after E2 and E2 plus flutamide administration compared with flutamide administration alone following T-H (P<0.05).
|
, but the levels were below 20 pg/ml in all groups and were not affected following administration of E2, flutamide, or the combination of E2 and flutamide (data not included).
In vitro cytokine secretion by AM
T-H produces a significant (P<0.05) release of TNF- (Fig. 4A
) and IL-6 (Fig. 4B)
by AM compared with the AM from the sham group. No significant differences in IL-10 (Fig. 4C)
secretion by AM were observed between the T-H group and respective sham animals (P>0.05). Administration of E2 and E2 plus flutamide led to a significant decrease in TNF- and IL-6 secretion by AM compared with the AM from the vehicle-treated T-H group (P<0.05). The production of IL-10 was not influenced significantly by the treatment regimens. Flutamide administration alone did not produce any significant reduction in TNF- release by AM compared with AM from vehicle-treated T-H animals (P>0.05).
|
after T-H (14.2±3.9 pg/ml) compared with the sham group (7.9±2.0 pg/ml). E2 (20.0±5.0 pg/ml), flutamide (24.3±9.2 pg/ml), and E2 plus flutamide (25.2±6.5 pg/ml) also had no significant effect on MCP-1 release in vitro by AM.
In vitro cytokine secretion by KC
T-H resulted in a significant increase of TNF- (Fig. 5A
) and IL-6 (Fig. 5B)
release by KC compared with the cells from the sham group (P<0.05). Treatment of animals with E2, flutamide, and E2 plus flutamide prevented this increase in TNF- secretion (P<0.05). Although treatment of mice with E2, flutamide, and E2 plus flutamide also reduced the release of IL-6 by KC following T-H, no significant differences were observed between vehicle-treated and E2-, flutamide-, and E2 plus flutamide-treated groups (Fig. 5A
and 5B)
.
|
, the release of IL-10 by KC was not found to be significantly different following T-H compared with shams. Treatment of animals with E2, flutamide, and E2 plus flutamide following T-H also did not significantly influence KC IL-10 release (Fig. 5C)
.
In vitro MCP-1 secretion by KC
MCP-1 secretion by KC following T-H was increased significantly in vehicle-treated animals compared with the sham group (P<0.05). Administration of E2 plus flutamide resulted in a significant reduction of MCP-1 secretion by KC (P<0.05). Furthermore, administration of E2 and flutamide led to a decrease in MCP-1 secretion by KC following T-H (Fig. 5D)
.
DISCUSSION
We examined the effects of flutamide and E2 administration following T-H on the release of pro- and anti-inflammatory cytokines by M from lung and liver and its association with organ damage and edema using mice that were in the metestrus state. The reason for selecting mice in the metestrus cycle was that we wanted to examine the effects of exogenous E2 on cytokines and organ damage in mice with the lowest level of estrogen. Moreover, as E2 levels are different in different cycles and are the highest in the proestrus cycle, the results would have been confounded by the presence of different and high levels of E2. Our results indicate that administration of E2, flutamide, and E2 plus flutamide following T-H in metestrus females resulted in a significant reduction of plasma TNF-, IL-6, and MCP-1 levels under those conditions. This reduction in plasma cytokines was associated with a decrease in the in vitro release of TNF-, IL-6, and MCP-1 by KC. Flutamide administration alone did not produce any significant decrease in systemic IL-10 levels; however, administration of E2 and E2 plus flutamide led to a significant reduction in plasma IL-10 levels. The in vitro release of proinflammatory cytokines by AM was reduced significantly if the mice were treated with E2 or E2 plus flutamide following T-H but not by the administration of flutamide alone. A significant decrease in pulmonary and hepatic edema formation was observed following E2, flutamide, or E2 plus flutamide administration, whereas neutrophil infiltration in liver was only reduced significantly after E2 or E2 and flutamide administration following T-H.
Previous studies have shown that the sex steroid hormonal milieu prevailing at the time of injury alters the function of M as evidenced by their ability to release inflammatory mediators (e.g., cytokines) [15
, 16
, 26
27
28
29
]. The increased release of inflammatory mediators by KC and immune depression of splenic M following T-H are known to be severe in adult males and aged and ovariectomized females as opposed to maintained immune functions in proestrus females with high systemic E2 concentrations. Furthermore, immune functions in ovariectomized females as well as males following T-H were found to be restored by E2 treatment [15
, 16
, 29
]. In line with these results, we were able to show that the administration of E2 following T-H resulted in a significant reduction of systemic cytokine and MCP-1 concentrations, which was associated with a marked decrease of in vitro cytokine release of AM and KC and a significant reduction in remote organ injury.
In contrast to E2, testosterone was shown to play an important role in the suppression of humoral and cell-mediated immunity following T-H [17 , 18 ]. In precastrated male mice, immune function was improved significantly compared with intact animals, whereas the administration of testosterone in castrated mice resulted in an immune dysfunction comparable with intact males [30 ]. Furthermore, administration of the androgen receptor antagonist flutamide following T-H restored immune function in males under those conditions [13 , 20 ]. Previous studies have shown that testosterone is also present in the circulation of females [31 ]. Furthermore, androgen receptors have been found on immune cells from male and female animals [22 , 32 ]. It could therefore be postulated that blockade of androgen receptors by flutamide should contribute to a reduction of immune dysfunction following T-H in females as it was observed in males. The results of this study suggest that there is indeed a beneficial effect of flutamide administration on immune function in females after T-H with a significant reduction of proinflammatory plasma cytokine concentrations, a decrease of in vitro cytokine release of KC, and a significant reduction of pulmonary and hepatic edema formation. However, administration of flutamide in combination with E2 did not produce any further significant improvement in immune function compared with the administration of E2 alone. This might be a result of the fact that testosterone levels in females are low compared with males, and the beneficial effects of administered E2 are much greater than the effects seen with blocking the androgen receptors by flutamide in females.
It is possible that flutamide might also contribute to the observed reduction of immune dysfunction in females by producing effects that are not dependent on androgen receptors. For instance, it is well known that E2 exerts its salutary effects on target organs by interacting with specific ER, such as ER- and -ß [33
, 34
]. Experimental studies have indicated that T-H has a significant influence on ER expression in males and females [18
, 22
]. In proestrus females, a marked attenuation of post-traumatic ER-ß expression in T-lymphocytes has been demonstrated [22
]. Furthermore, there is a significant decrease in ER- and -ß expression on cardiomyocytes and immune cells after T-H in males [18
, 22
]. Administration of flutamide, however, prevented this post-traumatic reduction in the ER expression without affecting the androgen receptor expression in male animals [18
, 22
]. The importance of the interaction between flutamide and the ER is enhanced further by the fact that blockade of the ER by the ER antagonist ICI182,780 abolished the salutary effects of flutamide on immune function [35
]. As M, such as KC and AM, also express these ER [33
, 34
, 36
], it might be suggested that flutamide, in addition to its possible role as an androgen receptor antagonist in females, exerts its beneficial effects by increasing E2 concentrations and the expression of ER following T-H, thereby mediating the salutary effects on immune function. However, we did not find a significant effect on immune function following the combined treatment of E2 and flutamide, which should be expected if flutamide indeed resulted in a significantly enhanced ER expression in females as observed in males [22
]. As additive effects were not observed, it can be speculated that the E2-mediated increase of ER expression might be the maximal, and thus, further ER expression is not possible with the additional ER expression that may be provided by flutamide.
Studies have also demonstrated that the intracrine synthesis of E2 from testosterone, which is mediated by aromatase, contributes significantly to altered release of cytokines by immune cells after T-H in males and females [22 , 32 ]. Furthermore, previous studies have also shown that administration of flutamide following T-H resulted in a significantly improved cardiac function [23 ]. Furthermore, it was demonstrated that post-traumatic flutamide administration was associated with a significant increase of cardiac aromatase activity and significantly increased E2 levels in the heart. Thus, it was concluded that the administration of flutamide after T-H increased E2 levels in the heart by conversion of testosterone and estrogen [23 ]. Flutamide administration in females might therefore also produce an increased local synthesis of E2 in immune cells and thus maintain the post-traumatic immune function of these cells.
Previous studies have indicated that KC are the major source of systemic cytokine levels [10 , 37 38 39 ]. Thus, it is not surprising that the increase in MCP-1 in the liver is higher than in the lung. Nonetheless, the role of other tissues/organs responsible for the increase in plasma MCP-1 levels has not been ruled out in this study. We recognize that our studies suggest a 100-fold increase in circulating MCP-1 versus fourfold increase in the liver; however, it should be noted that MCP-1 levels in the liver were measured by isolating KC, and it is difficult to compare LPS-stimulated MCP-1 secretion of in vitro by isolated cells with in vivo plasma levels of MCP-1. The precise role of liver-derived MCP-1 in plasma MCP-1 accumulation will only be established if those studies are performed in KC-depleted animals.
Although a role of MCP-1 in postinjury pathogenesis remains to be established, studies have shown that MCP-1 is critical in the migration of M and monocytes in experimental models of cecal ligation and puncture, peritonitis, and ischemia/reperfusion. Furthermore, MCP-1 can also activate M and endothelial cells. Recent studies have provided evidence that MCP-1 is involved in attracting neutrophils and causing neutrophil-dependent tissue damage. It is likely that MCP-1 may not directly attract neutrophils but may up-regulate neutrophil chemoattractants such as KC and MIP-2. Another potential pathway by which MCP-1 may modulate neutrophil-dependent tissue injury includes the regulation of ICAM-1. MCP-1 has been shown to up-regulate ICAM-1 expression on endothelial cells following ischemia-reperfusion [38
, 39
]. Based on these findings, it appears that MCP-1 and its increase in circulation may play role in mediating distant organ damage.
In conclusion, our results suggest that similar to E2, administration of flutamide also has salutary effects on the immune function after T-H in females. Although the potential mechanism by which flutamide mediates its action in females remains to be established, it is likely that flutamide mediates its salutary effects via blocking of androgen receptors; up-regulation of ER expression of immune cells; and/or increased local aromatase activity, which enhances the synthesis of E2. Further studies delineating the mechanism and with a longer post-traumatic observation period should help in determining whether administration of flutamide alone or in combination with E2 is an additive, therapeutic option for restoring and maintaining immune function after trauma.
ACKNOWLEDGEMENTS
This study was supported by NIH Grant R01 GM 37127.
FOOTNOTES
1 Current address: Trauma Department, Hannover Medical School, Hannover, Germany. 
Received April 6, 2006; revised May 5, 2006; accepted June 23, 2006.
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