Downregulation of TLR4‐dependent ATP production is critical for estrogen‐mediated immunoprotection in Kupffer cells following trauma‐hemorrhage

Hsieh, Ya Ching; Frink, Michael; Kawasaki, Takashi; Thobe, Bjoern M.; Choudhry, Mashkoor A.; Schwacha, Martin G.; Bland, Kirby I.; Chaudry, Irshad H.

doi:10.1002/jcp.20943

Cited by 34 publications

(28 citation statements)

References 39 publications

(46 reference statements)

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“…83 Chaudry and colleagues have found that estrogens have a positive effect on inflammation and hypermetabolism and improve survival in a trauma hemorrhage model. [84][85][86][87] In the present study, we found that estrogen was significantly decreased immediately after the injury but increased during hospital stay, while testosterone decreased and progesterone increased over time. Therefore, it would be interesting to investigate the effects of estrogen on the postburn response.…”

Section: Discussionsupporting

confidence: 58%

The Pathophysiologic Response to Severe Burn Injury.

Jeschke

Finnerty

Norbury

et al. 2006

Critical Care Medicine

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Objective-To improve clinical outcome and to determine new treatment options, we studied the pathophysiologic response postburn in a large prospective, single center, clinical trial.Summary Background Data-A severe burn injury leads to marked hypermetabolism and catabolism, which are associated with morbidity and mortality. The underlying pathophysiology and the correlations between humoral changes and organ function have not been well delineated.Methods-Two hundred forty-two severely burned pediatric patients [>30% total body surface area (TBSA)], who received no anabolic drugs, were enrolled in this study. Demographics, clinical data, serum hormones, serum cytokine expression profile, organ function, hypermetabolism, muscle protein synthesis, incidence of wound infection sepsis, and body composition were obtained throughout acute hospital course.Results-Average age was 8 ± 0.2 years, and average burn size was 56 ± 1% TBSA with 43 ± 1% third-degree TBSA. All patients were markedly hypermetabolic throughout acute hospital stay and had significant muscle protein loss as demonstrated by a negative muscle protein net balance (−0.05% ± 0.007 nmol/100 mL leg/min) and loss of lean body mass (LBM) (−4.1% ± 1.9%); P < 0.05. Patients lost 3% ± 1% of their bone mineral content (BMC) and 2 ± 1% of their bone mineral density (BMD). Serum proteome analysis demonstrated profound alterations immediately postburn, which remained abnormal throughout acute hospital stay; P < 0.05. Cardiac function was compromised immediately after burn and remained abnormal up to discharge; P < 0.05. Insulin resistance appeared during the first week postburn and persisted until discharge. Patients were hyperinflammatory with marked changes in IL-8, MCP-1, and IL-6, which were associated with 2.5 ± 0.2 infections and 17% sepsis.Conclusions-In this large prospective clinical trial, we delineated the complexity of the postburn pathophysiologic response and conclude that the postburn response is profound, occurring in a timely manner, with derangements that are greater and more protracted than previously thought.

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Section: Discussionsupporting

confidence: 58%

The Pathophysiologic Response to Severe Burn Injury.

Jeschke

Finnerty

Norbury

et al. 2006

Critical Care Medicine

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“…23 The results of the present study show that the ATP content of the kidneys in the shock group rats exhibited a downward trend at 90 min after hemorrhage and 0 h after resuscitation. We speculate that this trend may be related to hemorrhage-induced renal ischemia through the excitement of the sympathetic nerve and the adrenal medulla system, and the release of vasoactive substances; however, it needs new evidences.…”

Section: Discussionsupporting

confidence: 47%

Mesenteric lymph duct ligation after hemorrhagic shock enhances the ATP level and ATPase activity in rat kidneys

et al. 2014

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Background: Kidney injury commonly occurs following hemorrhagic shock. This study aims to observe the effects of mesenteric lymph duct ligation (MLDL) on the adenosine triphosphate (ATP) levels and the cell membrane adenosine triphosphatase (ATPase) activity in the kidneys of rats subjected to hemorrhagic shock. Methods: Wistar rats were assigned into sham, shock, and ligation groups. The hemorrhagic shock model was established in the shock and ligation groups, and MLDL was performed in the ligation group after resuscitation. Renal homogenates were prepared to determine the ATP and ATPase levels at 90 min after hemorrhage and at 0, 1, 3, 6, 12, and 24 h after resuscitation. Results: The ATP levels, and the Na

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“…Further, in vitro treatment of Kupffer cells with progesterone decreased TNF-α synthesis (107). In a recent study, it was found that Kupffer cell TLR4, iNOS, IL-6, and TNF-α production capacities were increased; and ATP, Tfam, and mitochondrial cytochrome oxidase I (mtCOI) levels were decreased following trauma-hemorrhage, whereas E2 administration normalized these levels (108). Furthermore, the decreased Kupffer cell ATP and mtCOI levels were not observed in TLR4 mutant mice following trauma-hemorrhage, suggesting that downregulation of TLR4-dependent ATP production is critical to E2-mediated immunoprotection in Kupffer cells following trauma-hemorrhage (108).…”

Section: Kupffer Cellsmentioning

confidence: 99%

“…In a recent study, it was found that Kupffer cell TLR4, iNOS, IL-6, and TNF-α production capacities were increased; and ATP, Tfam, and mitochondrial cytochrome oxidase I (mtCOI) levels were decreased following trauma-hemorrhage, whereas E2 administration normalized these levels (108). Furthermore, the decreased Kupffer cell ATP and mtCOI levels were not observed in TLR4 mutant mice following trauma-hemorrhage, suggesting that downregulation of TLR4-dependent ATP production is critical to E2-mediated immunoprotection in Kupffer cells following trauma-hemorrhage (108). Activation of TLR4 initiates an inflammatory cascade involving activation of p38 MAPK, phosphatidylinositol 3-kinase (PI3K), and NF-κB, leading to the release of proinflammatory cytokines (109)(110)(111).…”

Section: Kupffer Cellsmentioning

confidence: 99%

Estrogen: A Novel Therapeutic Adjunct for the Treatment of Trauma-Hemorrhage—Induced Immunological Alterations

Raju

Bland

Chaudry

2008

Mol Med

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ESTROGEN, MECHANISM OF ACTIONE2, the female hormone, is mainly produced by the ovaries and the placenta. The three major estrogens in women are estradiol, estriol, and estrone ( Figure 1). Estrogens are synthesized from androgens by the loss of C-19 angular methyl group and the formation of an aromatic A ring. Whereas estradiol is derived from testosterone, estrone is derived from androstenedione. The main form of E2 in women Trauma-hemorrhage leads to prolonged immune suppression, sepsis, and multiple organ failure. The condition affects all compartments of the immune system, and extensive studies have been carried out elucidating the immunological events following trauma-hemorrhage. The immune alteration observed following trauma-hemorrhage is gender dependent in both animal models and humans, though some studies in humans are contradictory. Within 30 min after trauma-hemorrhage, splenic and peritoneal macrophages, as well as T-cell function, are depressed in male animals, but not in proestrus females. Studies have also shown that the survival rate and the induction of subsequent sepsis following trauma-hemorrhage are significantly higher in males and ovariectomized females compared with proestrus females. These and other investigations show that sex hormones form the basis of this gender dichotomy, and administration of estrogen can ameliorate the immune depression and increase the survival rate after trauma-hemorrhage. This review specifically elaborates the studies carried out thus far demonstrating immunological alteration after trauma-hemorrhage and its modulation by estrogen. Also, estrogen was shown to produce its salutary effects through nuclear as well as extranuclear receptors. Estrogen rapidly activates several protein kinases and phosphatases, as well as the release of calcium in different cell types. The results of the studies exemplify the promise of estrogen as a therapeutic adjunct in treating adverse pathophysiological conditions following trauma-hemorrhage.

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Downregulation of TLR4‐dependent ATP production is critical for estrogen‐mediated immunoprotection in Kupffer cells following trauma‐hemorrhage

Cited by 34 publications

References 39 publications

The Pathophysiologic Response to Severe Burn Injury.

The Pathophysiologic Response to Severe Burn Injury.

Mesenteric lymph duct ligation after hemorrhagic shock enhances the ATP level and ATPase activity in rat kidneys

Estrogen: A Novel Therapeutic Adjunct for the Treatment of Trauma-Hemorrhage—Induced Immunological Alterations

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