Platelet-derived TLT-1 is a prognostic indicator in ALI/ARDS and prevents tissue damage in the lungs in a mouse model.
Pubmed ID: 30282800
Pubmed Central ID: PMC6284217
Publication Date: 12/06/2018
Affiliation: Department of Biology, University of Puerto Rico-Rio Piedras, San Juan, Puerto Rico.
MeSH Terms: Humans, Animals, Predictive Value of Tests, Acute Lung Injury, Mice, Disease Models, Animal, Blood Platelets, Mice, Knockout, Neutrophils, Neutrophil Infiltration, Receptors, Immunologic, Transendothelial and Transepithelial Migration, Respiratory Distress Syndrome
Grants: G12 MD007583, U54 MD007587, P20 GM103475, U54 HL112311, R01 HL090933, F31 HL136183, R01 HL126547, SC2 GM081237, K01 GM103806
Authors: Chen J, Morales-Ortíz J, Deal V, Reyes F, Maldonado-Martínez G, Ledesma N, Staback F, Croft C, Pacheco A, Ortiz-Zuazaga H, Yost CC, Rowley JW, Madera B, John AS, Lopez J, Rondina MT, Hunter R, Gibson A, Washington AV
Cite As: Morales-Ortíz J, Deal V, Reyes F, Maldonado-Martínez G, Ledesma N, Staback F, Croft C, Pacheco A, Ortiz-Zuazaga H, Yost CC, Rowley JW, Madera B, John AS, Chen J, Lopez J, Rondina MT, Hunter R, Gibson A, Washington AV. 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. Epub 2018 Oct 3.
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 (<i>P</i> < .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 (<i>P</i> < .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% (<i>P</i> ≤ .001) and tissue damage by 25% (<i>P</i> ≤ .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.