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Am J Physiol Lung Cell Mol Physiol 292: L1227-L1232, 2007. First published February 2, 2007; doi:10.1152/ajplung.00479.2006
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Downregulation of migration inhibitory factor is critical for estrogen-mediated attenuation of lung tissue damage following trauma-hemorrhage

Ya-Ching Hsieh, Michael Frink, Chi-Hsun Hsieh, Mashkoor A. Choudhry, Martin G. Schwacha, Kirby I. Bland, and Irshad H. Chaudry

Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama

Submitted 15 December 2006 ; accepted in final form 25 January 2007


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Although studies have shown that 17beta-estradiol (E2) prevents neutrophil infiltration and organ damage following trauma-hemorrhage, the mechanism by which E2 inhibits neutrophil transmigration remains unknown. Macrophage migration inhibitory factor (MIF) is thought to play a central role in exacerbation of inflammation and is associated with lung injury. MIF regulates the inflammatory response through modulation of Toll-like receptor 4 (TLR4). Activation of TLR4 results in the release of proinflammatory cytokines and chemokines, which induce neutrophil infiltration and subsequent tissue damage. We hypothesized that E2 mediates its salutary effects in the lung following trauma-hemorrhage via negative regulation of MIF and modulation of TLR4 and cytokine-induced chemotaxis. C3H/HeOuJ mice were subjected to trauma-hemorrhage (mean blood pressure 35 ± 5 mmHg for ~90 min, then resuscitation) or sham operation. Mice received vehicle, E2, or E2 in combination with recombinant mouse MIF protein (rMIF). Trauma-hemorrhage increased lung MIF and TLR4 protein levels as well as lung and systemic levels of cytokines/chemokines. Treatment of animals with E2 following trauma-hemorrhage prevented these changes. However, administration of rMIF protein with E2 abolished the E2-mediated decrease in lung TLR4 levels, lung and plasma levels of IL-6, TNF-{alpha}, monocyte chemoattractant protein-1, and keratinocyte-derived chemokine (KC). Administration of rMIF protein also prevented E2-mediated reduction in neutrophil influx and tissue damage in the lungs following trauma-hemorrhage. These results suggest that the protective effects of E2 on lung injury following trauma-hemorrhage are mediated via downregulation of lung MIF and TLR4-induced cytokine/chemokine production.

hemorrhagic shock; 17beta-estradiol; Toll-like receptor 4; myeloperoxidase; cytokines; chemokines

DESPITE NUMEROUS ADVANCES in intensive care medicine, ischemia-reperfusion, sepsis, and organ dysfunction leading to multiple organ failure remain the major causes of death after trauma (1, 20, 23, 31, 32). Hemorrhagic shock is a major contributor to the development of acute respiratory distress syndrome (ARDS) in patients who sustain major mechanical trauma (30). Cellular dysfunction following hemorrhagic shock occurs in many organs, including the lung, and such alterations persist for a prolonged period of time despite fluid resuscitation (22, 42). There is increasing evidence that hormonal mechanisms are involved in regulating the posttraumatic lung neutrophil infiltration and injury. In this regard, studies have shown that males exhibit an increase in lung neutrophil infiltration following trauma-hemorrhage (14). In contrast, females in the proestrus state did not show any increase in lung neutrophil infiltration under those conditions (47). Moreover, administration of 17beta-estradiol (E2) in male mice following trauma-hemorrhage attenuated lung tissue damage (14, 18). However, the precise mechanism by which E2 prevents organ damage after trauma-hemorrhage is not known.

Migration inhibitory factor (MIF) is a proinflammatory cytokine released by macrophages and T lymphocytes and activates immune responses (4). MIF has been confirmed to be ubiquitously expressed in a variety of cells and tissues and has been shown to be important in regulating immune/inflammatory response (34, 41, 43). Moreover, MIF has been shown to be upregulated in the wound-healing process of estrogen-deficient mice, and estrogen has been shown to decrease MIF production by murine macrophages (3). MIF has also been reported to play a central role in exacerbation of inflammation and sepsis (6, 8) and is associated with lung injury (26). In patients with ARDS, MIF has been reported to be present in the affected lungs, and the alveolar macrophages are one cellular source of MIF (9). A recent report has suggested that gene expression of Toll-like receptor 4 (TLR4) in macrophages can be upregulated by MIF (39). TLRs are a group of pattern recognition receptors that recognize conserved molecular motifs found in a variety of organisms including bacteria, viruses, and fungi (5, 21). TLR4 is the dominant mammalian receptor for the microbial product lipopolysaccharide (LPS) (37). Moreover, activation of TLR4 leads to the release of proinflammatory cytokines and chemokines (2, 35). The induced cytokines/chemokines can mediate systemic responses and recruit leukocytes to the site of inflammation (2, 35).

Studies have demonstrated that the enhanced secretion of proinflammatory cytokines by mast cells, dendritic cells, and macrophages is an important factor in the initiation and perpetuation of lung inflammation (10). These cytokines recruit other immune cells including neutrophils, thereby increasing leukocyte trafficking and lung permeability (45). Neutrophils can release mediators, which diffuse across the endothelium and damage parenchymal cells (36). Cytokines, such as TNF-{alpha}, upregulate chemokines, setting the stage for neutrophil migration through endothelium (11). The chemokine monocyte chemoattractant protein-1 (MCP-1) acts by binding to the MCP-1 receptor, which promotes both the maturation of monocytes to macrophages as well as their chemotactic recruitment (17). Additionally, keratinocyte-derived chemokine (KC) is a major cytokine-inducible neutrophil chemoattractant (25). KC function is essential to neutrophil emigration in response to LPS in the alveolar air spaces (12).

In this study, we investigated whether E2 attenuates lung injury following trauma-hemorrhage via regulation of MIF and TLR4-induced cytokine/chemokine production under those conditions. To test this hypothesis, the effect of E2 either alone or in combinations with recombinant MIF protein (rMIF) in mice following trauma-hemorrhage were examined on: 1) lung MIF and TLR4 levels; 2) lung contents and systemic levels of IL-6, TNF-{alpha}, MCP-1, and KC; and 3) lung neutrophil myeloperoxidase (MPO) activity and lung edema formation.


   MATERIALS AND METHODS
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 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Trauma-hemorrhagic shock model. Male C3H/HeOuJ mice (8–12 wk old) were purchased from the Jackson Laboratories (Bar Harbor, ME). Mice were fasted overnight but allowed water ad libitum. They were anesthetized with isoflurane (Minrad, Bethlehem, PA) and restrained in a supine position. A midline laparotomy (2 cm) was performed, which was then closed in two layers with sutures (Ethilon 6–0; Ethicon, Somerville, NJ). Both femoral arteries and the right femoral vein were cannulated with polyethylene tubing (Becton Dickinson, Sparks, MD). Blood pressure was measured via an arterial catheter using a blood pressure analyzer (Micro-Med, Louisville, KY). On awakening, animals were bled rapidly through the other arterial catheter to a mean arterial blood pressure of 35 ± 5 mmHg within 10 min, which was then maintained for 90 min. At the end of that interval, the animals were resuscitated via the venous line with four times the shed blood volume using Ringer lactate. After ligating the blood vessels, catheters were removed; the incisions were flushed with lidocaine and closed with sutures. Sham-operated animals underwent the same surgical procedures but were neither hemorrhaged nor resuscitated. The animals were killed at 4 h after resuscitation or sham operation. In the treatment group, E2 (50 µg/25 g) or vehicle (10% DMSO) (Sigma, St. Louis, MO) was administered subcutaneously at the onset of resuscitation. In another group of mice, rMIF protein (25 µg/25 g body wt; R&D Systems, Minneapolis, MN) was given intraperitoneally at the beginning of the resuscitation with E2 treatment. Sham group included E2- and vehicle-treated animals, and no difference was observed between E2 and vehicle in shams. All experiments were carried out in accordance to the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee of the University of Alabama at Birmingham.

Tissue harvesting and preparation of tissue homogenates. The mice were anesthetized with isoflurane 4 h after sham operation or resuscitation in the trauma-hemorrhage groups, and blood was obtained via cardiac puncture using a syringe coated with EDTA (Sigma). Blood was centrifuged (2,500 g, 10 min, 4°C), and the plasma was stored at –80°C. Lungs were removed aseptically, frozen in liquid nitrogen, and stored at –80°C. Frozen lung tissue samples were thawed and suspended in lysis buffer comprising of 50 mM HEPES (pH 7.5), 150 mM NaCl, 1.5 mM MgCl2, 1 mM EDTA, 100 mM NaF, 0.2 mM Na3VO4, 10 mM Na4P2O7, 0.5% Triton X-100, 10% glycerol, and 1% proteinase inhibitor cocktail (Sigma). The samples were sonicated on ice (Sonic Dismembrator; Fisher Scientific, Hampton, NH) and centrifuged at 12,000 g for 10 min at 4°C. The supernatants were then frozen and stored at –80°C until further assayed. Aliquots were used to determine protein concentration (DC Protein Assay, Bio-Rad, Hercules, CA).

Cytokine analysis. The concentrations of cytokines/chemokines in the plasma and lung tissue homogenates were determined with Cytokine Bead Array inflammatory kits using flow cytometry according to the manufacturer's instructions (BD Pharmingen, San Diego, CA) as described previously (14). Briefly, 50 µl of mixed capture beads were incubated with 50-µl samples for 1 h at 25°C, and then 50 µl of mixed PE detection reagent was added. After incubation for 1 h at 25°C in the dark, the complexes were washed twice and analyzed using the LSR II flow cytometer (BD Biosciences, Mountain View, CA). Data analysis was carried out using the accompanying FACSDiva and FCAP Array software (BD Biosciences). Tissue cytokine/chemokine contents were normalized to protein concentration.

MPO assay. The accumulation of neutrophils in the lung tissue was assessed by measuring the MPO activity as previously described (14). Frozen tissue samples were thawed and suspended in 10% phosphate buffer (pH 6.0) containing 1% hexadecyltrimethylammonium bromide (Sigma). The samples were sonicated on ice, centrifuged at 12,000 g for 15 min at 4°C, and an aliquot (30 µl) was transferred into 180-µl phosphate buffer (pH 6.0) containing 0.167 mg/ml o-dianisidine dihydrochloride and 0.0005% hydrogen peroxide (Sigma). The change in absorbance at 460 nm was measured spectrophotometrically for 10 min. MPO activity was calculated using a standard curve that was generated using human MPO (Sigma), and values were normalized to protein concentration.

Determination of tissue wet-to-dry ratios. Wet-to-dry weight ratios of lungs were used as a parameter of tissue edema. Tissue samples were weighed immediately after removal (wet weight) and then subjected to desiccation in an oven at 80°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.

Statistical analysis. Data are presented as means ± SE. One-way analysis of variance (ANOVA) and Tukey's test were employed for the comparison among groups.


   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Lung MIF protein levels. Trauma-hemorrhage led to a significant increase of MIF protein content in lung tissue of vehicle-treated animals compared with shams (Fig. 1; P < 0.05). This increase was markedly diminished by E2 treatment. However, coadministration of rMIF in E2-treated animals prevented the decrease in lung MIF protein levels following trauma-hemorrhage (P < 0.05).


Figure 1
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  		Fig. 1. Lung macrophage migration inhibitory factor (MIF) protein levels following trauma-hemorrhage. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as a protein loading control. Blots obtained from several experiments were analyzed using densitometry, and the densitometric values were pooled from 4 to 6 animals in each group and are shown as means ± SE in the bar graph. Data are analyzed by one-way ANOVA and Tukey's test. T-H vehicle, trauma-hemorrhage vehicle; T-H E2, trauma-hemorrhage 17beta-estradiol (E2); T-H E2+rMIF, trauma-hemorrhage E2 + recombinant mouse MIF (macrophage MIF). *P < 0.05 vs. sham.

 
Lung TLR4 protein levels. As shown in Fig. 2, TLR4 protein levels in lungs were increased significantly (P < 0.05) in the vehicle-treated trauma-hemorrhage group compared with shams. E2 administration following trauma-hemorrhage attenuated the increase in TLR4 levels, which was prevented by administration of rMIF protein (P < 0.05).


Figure 2
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  		Fig. 2. Lung Toll-like receptor 4 (TLR4) protein levels following trauma-hemorrhage. GAPDH was used as a loading control. Blots obtained from several experiments were analyzed using densitometry, and the densitometric values were pooled from 4 to 6 animals in each group and are shown as means ± SE in the bar graph. Data are analyzed by one-way ANOVA and Tukey's test. *P < 0.05 vs. sham.

 
Lung cytokine and chemokine contents. Lung contents of IL-6 (Fig. 3A), TNF-{alpha} (Fig. 3B), MCP-1 (Fig. 3C), and KC (Fig. 3D) were increased following trauma-hemorrhage in vehicle-treated animals (P < 0.05) compared with shams. Treatment of trauma-hemorrhage mice with E2 markedly decreased IL-6, TNF-{alpha}, MCP-1, and KC contents following trauma-hemorrhage. However, coadministration of rMIF protein abolished the inhibitory effect of E2 on lung cytokine and chemokine levels (P < 0.05).


Figure 3
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  		Fig. 3. Lung cytokine/chemokine contents of interleukin (IL)-6 (A), tumor necrosis factor-{alpha} (TNF-{alpha}) (B), monocyte chemoattractant protein (MCP-1) (C), and keratinocyte-derived chemokine (KC) (D) following trauma-hemorrhage. Cytokine contents are shown as means ± SE of 4–6 animals in each group in the bar graph. Data are compared by one-way ANOVA and Tukey's test. *P < 0.05 vs. sham.

 
Plasma cytokine and chemokine concentrations. Plasma concentrations of IL-6 (Fig. 4A), TNF-{alpha} (Fig. 4B), MCP-1 (Fig. 4C), and KC (Fig. 4D) were elevated following trauma-hemorrhage in vehicle-treated animals (P < 0.05) compared with shams. E2 treatment markedly decreased plasma concentrations of IL-6, TNF-{alpha}, MCP-1, and KC contents in trauma-hemorrhage mice. Coadministration of rMIF protein prevented the E2-mediated decrease in plasma cytokine and chemokine levels (P < 0.05).


Figure 4
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  		Fig. 4. Plasma concentrations of IL-6 (A), TNF-{alpha} (B), MCP-1 (C), and KC (D) following trauma-hemorrhage. Values are means ± SE of 4–6 animals in each group. Data are analyzed by one-way ANOVA and Tukey's test. *P < 0.05 vs. sham; #P < 0.05 vs. T-H vehicle.

 
MPO activity and wet-to-dry weight ratio. Trauma-hemorrhage increased MPO activity in lungs of vehicle-treated animals (Fig. 5; P < 0.05) compared with shams, which was reduced by treatment of animals with E2 (P < 0.05). Administration of rMIF protein abolished the E2-mediated reduction in MPO activity following trauma-hemorrhage (P < 0.05). Lung tissue edema formation was also increased in vehicle-treated trauma-hemorrhage animals (Fig. 6; P < 0.05). The increase in the wet-to-dry weight ratio was reduced by treatment with E2 following trauma-hemorrhage. Administration of rMIF protein to trauma-hemorrhage mice abolished the E2 mediated the decrease in lung tissue edema formation (P < 0.05).


Figure 5
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  		Fig. 5. MPO activity in lung tissue following trauma-hemorrhage. Values are means ± SE of 4–6 animals in each group. Data are normalized to protein contents and are compared by one-way ANOVA and Tukey's test. *P < 0.05 vs. sham; #P < 0.05 vs. T-H vehicle.

 

Figure 6
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  		Fig. 6. Edema formation in lung tissue following trauma-hemorrhage. Wet-to-dry weight ratios of lung tissue were used as a measure of tissue edema. Values are means ± SE of 4–6 animals in each group. Data are compared by one-way ANOVA and Tukey's test. *P < 0.05 vs. sham.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
This study was undertaken to determine the role of MIF in E2-mediated protective effects on lung tissue damage following trauma-hemorrhage. Our results showed that 4 h following trauma-hemorrhage, lung MIF and TLR4 protein levels, as well as cytokine/chemokine levels, were markedly increased, which was prevented by E2 treatment. Coadministration of rMIF protein abolished the E2-mediated decrease in lung TLR4 levels as well as lung and plasma levels of IL-6, TNF-{alpha}, MCP-1, and KC, and circulating IL-6, TNF-{alpha}, MCP-1, and KC levels. Administration of rMIF protein also prevented E2-mediated reduction in neutrophil influx and edema formation in the lungs following trauma-hemorrhage. These results indicate that MIF plays a major role in E2-mediated amelioration of organ damage following trauma-hemorrhage. Furthermore, our findings suggest that MIF mediates its effect by upregulation of TLR4 and cytokine-induced chemotaxis following trauma-hemorrhage.

Elevated local MIF is associated with an increased inflammatory response and markedly delayed wound healing. However, this can be entirely reversed by exogenous E2 treatment (16). The expression of MIF is upregulated in the lung tissues, and inhibition of MIF remarkably reduces the severity of lung injury in a model of LPS-induced pulmonary injury (26). In addition, MIF has been demonstrated to profoundly affect the expression of TLR4 in RAW 267.4 macrophages (39). Knockdown of MIF expression with MIF antisense results in the downregulation of TLR4 mRNA and protein levels in macrophages. In addition, MIF antisense suppresses TLR4 promoter activity and TNF production. The work of Roger et al. (40) has demonstrated that MIF regulates host responses to endotoxin through modulation of TLR4 in macrophages. In the current study, trauma-hemorrhage resulted in an increase in lung MIF and TLR4 protein levels, which was prevented by E2 treatment. Administration of rMIF protein, however, abolished the E2-mediated decrease in lung TLR4 levels following trauma-hemorrhage. Thus it is likely that E2 attenuates lung tissue damage via downregulation of MIF through modulation of TLR4 following trauma-hemorrhage.

It has also been reported that MIF modulates neutrophil accumulation in the lungs in an acute pneumonitis rat model, suggesting that MIF expression contributes to the recruitment of neutrophils at inflammatory loci and promotes acute inflammation (26). On the other hand, TLR4 has been implicated in such diverse processes as cytokine/chemokine production (33), phagocytic cell recruitment and function (27), and the generation of adaptive immunity (28). Activation of TLR4 results in a stimulus-specific expression of genes required to control infection and injury, including the production of inflammatory cytokines and chemokines, complement products, and the recruitment of neutrophils to the site of injury (27, 28, 32). Our (19) previous studies have shown that activation of TLR4 leads to increased production of circulating IL-6, TNF-{alpha}, MCP-1, and KC, as well as lung tissue damage following hemorrhagic shock. We (17) also found that pretreatment of mice with anti-MCP-1 antiserum prevented upregulation of KC, neutrophil infiltration, and edema in lung tissue following trauma-hemorrhage. Alternatively, restitution of KC abolished the beneficial effects of anti-MCP-1 antiserum on lung neutrophil infiltration and tissue damage (13). Other investigators have indicated that KC is essential to neutrophil emigration in response to LPS in the alveolar air spaces (12). Furthermore, neutrophil emigration is presumably initiated and modulated by the production of early response cytokines and chemokines from lung cells (15). Neutrophil infiltration has been indicated to be a key step in the development of organ damage or dysfunction following trauma-hemorrhage (17, 44). In this study, we found that administration of rMIF abolished E2-mediated downregulation of lung TLR4 levels as well as lung and circulating levels of IL-6, TNF-{alpha}, MCP-1, and KC. This was accompanied by increased lung neutrophil infiltration and lung wet-to-dry weight ratio, a parameter for tissue damage. These findings therefore suggest that E2 reduces lung neutrophil infiltration and subsequently attenuates tissue damage via negative regulation of MIF through modulation of TLR4-induced cytokines/chemokines production following trauma-hemorrhage. In addition, lung injury is associated with an increase in systemic cytokines (7, 38) and can initiate or exacerbate a systemic inflammatory response (29). Thus the E2-mediated reduction in lung tissue damage may contribute to the deceased systemic inflammatory response following trauma-hemorrhage.

It should be noted, however, that although rMIF abolished the E2-induced downregulation of MIF, thereby indicating that the effects of E2 are mediated via MIF, inhibition of MIF upregulation by using the neutralizing anti-MIF antibody should provide additional proof that downregulation of MIF plays a pivotal role in producing the effect of estrogen on attenuation of lung tissue damage following trauma-hemorrhage. However, anti-MIF neutralizing antibody is not yet available commercially, and thus in the absence of that, it is difficult to perform such a study. Nonetheless, it has been reported that treatment with rMIF alone failed to induce cytokine expression in the fibroblasts, and it also did not affect the cell survival rate under normal condition. Thus it would be expected that administration of MIF by itself, without E2 or trauma-hemorrhage, will not have any adverse effects in normal animals (24, 46). Although we did not test whether administration of rMIF in normal animals without shock or E2 has any adverse effects, the present study supports the concept that modulating cytokine/chemokine production could serve as a novel therapeutic target for the treatment of posttraumatic immunological and inflammatory alterations.

In summary, our study demonstrated that administration of rMIF abolished the effects of E2 on lung TLR4 levels as well as lung and circulating levels of cytokines/chemokines following trauma-hemorrhage. Administration of rMIF also prevented the E2-mediated reduction in lung neutrophil infiltration and tissue damage following trauma-hemorrhage. This study suggests that MIF plays a major role in E2-mediated lung protection following trauma-hemorrhage.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by National Institute of General Medical Sciences Grant R01-GM-37127. M. Schwacha is in part supported by National Institute of Allergy and Infectious Diseases Grant KO2-AI-049960.


   ACKNOWLEDGMENTS
 
We thank Connie Weldon for valuable help in editing the manuscript.


   FOOTNOTES
 

Address for reprint requests and other correspondence: I. H. Chaudry, Center for Surgical Research, Univ. of Alabama at Birmingham, 1670 Univ. Blvd., Volker Hall, Rm. G094, Birmingham, AL 35294-0019 (e-mail: Irshad.Chaudry{at}ccc.uab.edu)

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.


   REFERENCES
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 DISCUSSION
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 REFERENCES
 

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