Platelet-derived TLT-1 is a prognostic indicator in ALI/ARDS and prevents tissue damage in the lungs in a mouse model

Blood. 2018 Dec 6;132(23):2495-2505. doi: 10.1182/blood-2018-03-841593. Epub 2018 Oct 3.

Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) affect >200 000 individuals yearly with a 40% mortality rate. Although platelets are implicated in the progression of ALI/ARDS, their exact role remains undefined. Triggering receptor expressed in myeloid cells (TREM)-like transcript 1 (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 soluble TLT-1 (sTLT-1) from the ARDS Network clinical trial and show that patients whose sTLT-1 levels were >1200 pg/mL had nearly twice the mortality risk as those with <1200 pg/mL (P < .001). After correcting for confounding factors such as creatinine levels, Acute Physiology And Chronic Health Evaluation III scores, age, platelet counts, and ventilation volume, sTLT-1 remains significant, suggesting that sTLT-1 is an independent prognostic factor (P < .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% vs 8.92 ± 2.4% in wild-type mice), which correlated with increased neutrophil death. Infusion of sTLT-1 restores normal fibrinogen deposition and reduces pulmonary hemorrhage by 40% (P ≤ .001) and tissue damage by 25% (P ≤ .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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acute Lung Injury / blood*
  • Acute Lung Injury / pathology
  • Animals
  • Blood Platelets / metabolism*
  • Blood Platelets / pathology
  • Disease Models, Animal
  • Humans
  • Mice
  • Mice, Knockout
  • Neutrophil Infiltration
  • Neutrophils / metabolism
  • Neutrophils / pathology
  • Predictive Value of Tests
  • Receptors, Immunologic / blood*
  • Respiratory Distress Syndrome, Adult / blood*
  • Respiratory Distress Syndrome, Adult / pathology
  • Transendothelial and Transepithelial Migration

Substances

  • Receptors, Immunologic
  • TREML1 protein, human
  • Treml1 protein, mouse