title: Genetic deletion of toll-like receptor 4 on platelets attenuates experimental pulmonary hypertension.
abstract: BACKGROUND
  Recent studies demonstrate a role for toll-like receptor 4 (TLR4) in the pathogenesis of pulmonary hypertension (PH); however, the cell types involved in mediating the effects of TLR4 remain unknown.
  
  
  OBJECTIVE
  The objective of this study was to determine the contribution of TLR4 expressed on nonparenchymal cells to the pathogenesis of PH.
  
  
  RESULTS
  TLR4 bone marrow chimeric mice revealed an equal contribution of TLR4 on nonparenchymal and parenchymal cells in the pathogenesis of PH as determined by measuring right ventricular (RV) systolic pressure and RV hypertrophy. However, the deletion of TLR4 from myeloid lineage cells had no effect on the development of PH because we found no difference in RV systolic pressure or RV hypertrophy in wild-type versus LysM-TLR4(-/-) mice. To explore the potential role of platelet TLR4 in the pathogenesis of PH, platelet-specific TLR4(-/-) mice were generated (PF4-TLR4(-/-) mice). TLR4(-/-) platelets from either global TLR4(-/-) or PF4-TLR4(-/-) mice were functional but failed to respond to lipopolysaccharide, demonstrating a lack of TLR4. PF4-TLR4(-/-) mice demonstrated significant protection from hypoxia-induced PH, including attenuated increases in RV systolic pressure and RV hypertrophy, decreased platelet activation, and less pulmonary vascular remodeling. The deletion of TLR4 from platelets attenuated serotonin release after chronic hypoxia, and lipopolysaccharide-stimulated platelets released serotonin and promoted pulmonary artery smooth muscle cell proliferation in a serotonin-dependent manner.
  
  
  CONCLUSIONS
  Our data demonstrate that TLR4 on platelets contributes to the pathogenesis of PH and further highlights the role of platelets in PH.
authors.affiliation: From the Department of Surgery (E.M.B., R.S.C., C.P.S., D.J.H., T.R.B., P.M.B.), University of Pittsburgh Cancer Institute (E.M.B.), Division of Pediatric Surgery, Children's Hospital Pittsburgh (C.P.S., D.J.H.), Department of Pharmacology and Chemical Biology (P.M.B.), and Vascular Medicine Institute (P.M.B.), University of Pittsburgh School of Medicine, PA.
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Bauer
authors.forename: R Savanh
authors.initials: RS
authors.lastname: Chanthaphavong
authors.forename: Chhinder P
authors.initials: CP
authors.lastname: Sodhi
authors.forename: David J
authors.initials: DJ
authors.lastname: Hackam
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.forename: Philip M
authors.initials: PM
authors.lastname: Bauer
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology*; D018920:Coculture Techniques; D017353:Gene Deletion; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000235:genetics* / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000473:pathology / Q000502:physiology; D011828:Radiation Chimera; D051197:Toll-Like Receptor 4 / Q000097:blood / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
chemical_list: C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4
keywords: blood platelets; hypertension, pulmonary; toll-like receptor 4