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Emerging Role for TLT-1 Between the Interception of Inflammatory Hemorrhage and Hemostasis
Başlık:
Emerging Role for TLT-1 Between the Interception of Inflammatory Hemorrhage and Hemostasis
Yazar:
Morales-Ortiz, Jessica, author.
ISBN:
9780438081482
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (224 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-11(E), Section: B.
Advisors: Anthony V. Washington Committee members: José Agosto; Suranganie Dharmawardhane; Loyda B. Méndez; Matthew T. Rondina.
Özet:
Platelets are key players of hemostasis and inflammation. Inflammatory responses often induce hemostatic function through mechanisms that are not always understood. Triggering Receptor Expressed in Myeloid cells (TREM)-Like Transcript (TLT)-1 is found on alpha-granules of resting platelets, binds fibrinogen upon platelet activation, and mediates clot formation. TLT-1 deletion leads to hemorrhage after lipopolysaccharide and TNF-alpha treatment. To dissect the role of TLT-1 in hemostasis, thrombosis and inflammation, we used a CXCL-2 mediated local inflammatory reaction in the vessels of the cremaster muscle of treml1-/- and wild type mice. The absence of TLT-1 resulted in a 50% reduction in clot size and increased extravasation of plasma molecules in treml1-/- mice compared to wild type in inflamed cremaster muscle. TLT-1 deficiency also associated to a 2X reduction in integrin beta3 phosphorylation on residue Y773 after platelet activation. Using the Reverse Arthus Reaction, we demonstrated a role for TLT-1 on inflammatory-associated bleeding. In addition, we established a role for TLT-1 in thrombosis using the thromboplastin initiated and collagen/epinephrine models of pulmonary embolism. We retrospectively measured plasma levels of sTLT-1 from the ARDS-NET clinical trial and demonstrated that high levels of sTLT-1 (>1200pg/mL) is an independent-risk factor for ARDS associated mortality (Log Rank p < 0.0001). We used a murine lipopolysaccharide-induced ALI model and demonstrate delayed neutrophil transmigration, uncontrolled neutrophil accumulation and pulmonary tissue damage the absence of TLT-1. In vitro studies demonstrated that the absence of TLT-1 results in increased platelet-neutrophil conjugates (40.7+/-4.2% versus 10+/-4.8% in WT mice), together with increased neutrophil death, and tissue damage. The administration of sTLT-1 to the treml1-/- mice resulted in the reduction of pulmonary hemorrhage by 40% (p≤0.001) and tissue damage by 25% (p≤0.001) in vivo. Finally, we demonstrated that TLT-1 regulates fibrinogen abundance in plasma and communicates with P-selectin during platelet mediated immune responses. TLT-1 and P-selectin double knockout restored the proper neutrophil transmigration and prevented inflammatory associated hemorrhage in a fibrinogen dependent manner. Therefore, our findings demonstrate that TLT-1 governs the transition between hemostasis and immune responses during inflammation and hemostasis using an anticipatory strategy to facilitate controlled leukocyte transmigration to the inflammatory site.
Notlar:
School code: 0281
Tüzel Kişi Ek Girişi:
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(695198.1) | 695198-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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