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TLT-1 is a Prognostic Indicator in ALI/ARDS and Prevents Tissue Damage in the Lungs in a Mouse model

Jessica Morales-Ortíz, Victoria Deal, Fiorella Reyes, Gerónimo Maldonado-Martínez, Nahomy Ledesma, Franklin Staback, Cheyanne Croft, Amanda Pacheco, Humberto Ortiz-Zuazaga, C. Christian Yost, Jesse W. Rowley, Bismark Madera, Alex St. John, Junmei Chen, Jose Lopez, Matthew T. Rondina, Robert Hunter, Angela Gibson and A. Valance Washington

Key points

  • TLT-1 is an independent risk factor for ARDS.

  • In an ALI model TLT-1 mediates fibrinogen deposition in the lungs and facilitates platelet-neutrophil release during transmigration.

Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) affect over 200,000 individuals yearly with a 40% mortality rate. While platelets are implicated in the progression of ALI/ARDS, their exact role remains undefined. Triggering Receptor Expressed in Myeloid cells (TREM)-Like Transcript (TLT)-1 is found on platelets, binds fibrinogen, and mediates clot formation. We hypothesized that platelets use TLT-1 to manage the progression of ALI/ARDS. Here we retrospectively measure plasma levels of sTLT-1 from the ARDSNET clinical trial and show that patients whose sTLT-1 levels were >1200pg/mL had nearly twice the mortality risk as those with <1200 pg/mL (p<0.001). After correcting for confounding factors such as creatinine levels, APACHE III scores, age, platelet counts, and ventilation volume, sTLT-1 remains significant; suggesting that sTLT-1 is an independent prognostic factor (p < 0.0001). These data point to a role for TLT-1 during the progression of ALI/ARDS. We use a murine lipopolysaccharide-induced ALI model and demonstrate increased alveolar bleeding, aberrant neutrophil transmigration and accumulation associated with decreased fibrinogen deposition and increased pulmonary tissue damage in the absence of TLT-1. The loss of TLT-1 resulted in an increased proportion of platelet-neutrophil conjugates (43.73±24.75% versus 8.92±2.4% in WT mice), which correlated with increased neutrophil death. Infusion of sTLT-1 restores normal fibrinogen deposition and reduces pulmonary hemorrhage by 40% (p≤0.001) and tissue damage by 25% (p≤0.001) in vivo. Our findings suggest that TLT-1 uses fibrinogen to govern the transition between inflammation and hemostasis and facilitate controlled leukocyte transmigration during the progression of ARDS.

  • Submitted March 26, 2018.
  • Accepted September 14, 2018.