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This Article Full Text Full Text (PDF) All Versions of this Article: 292/5/L1227    most recent 00479.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Hsieh, Y.-C. Articles by Chaudry, I. H. Search for Related Content PubMed PubMed Citation Articles by Hsieh, Y.-C. Articles by Chaudry, I. H.

Downregulation of migration inhibitory factor is critical for estrogen-mediated attenuation of lung tissue damage following trauma-hemorrhage

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

Although studies have shown that 17-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-, 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; 17-estradiol; Toll-like receptor 4; myeloperoxidase; cytokines; chemokines

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