Modifications of cellular responses to lysophosphatidic acid and platelet-activating factor by plasma gelsolin.
Gelsolin is a highly conserved intracellular actin-binding protein with an extracellular isoform, plasma gelsolin (pGSN). Blood concentrations of pGSN decrease in response to diverse tissue injuries. Depletion of pGSN to critical levels precedes and often predicts complications of injuries such as lung permeability changes and death. Administration of recombinant pGSN ameliorates such complications and reduces mortality in animal models. One proposed mechanism for pGSN's protective effects is that it inhibits inflammatory mediators generated during primary injuries, since pGSN binds bioactive mediators, including lysophospatidic acid (LPA) and endotoxin in vitro. However, no direct evidence in support of this hypothesis has been available. Here we show that recombinant pGSN modestly inhibited LPA-induced P-selectin upregulation by human platelets in the presence of albumin (P < 0.0001). However, physiologically relevant pGSN concentrations inhibit platelet-activating factor (PAF)-mediated P-selectin expression by up to 77% (P < 0.0001). pGSN also markedly inhibited PAF-induced superoxide anion (O(2)(-)) production of human peripheral neutrophils (PMN) in a concentration-dependent manner (P < 0.0001). A phospholipid-binding peptide derived from pGSN (QRLFQVKGRR) also inhibited PAF-mediated O(2)(-) generation (P = 0.024). Therefore, pGSN interferes with PAF- and LPA-induced cellular activation in vitro, suggesting a mechanism for the protective role of pGSN in vivo.
Osborn
Teresia M
TM
Translational Medicine Division/ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115, USA. tmagnuson@rics.bwh.harvard.edu
Dahlgren
Claes
C
Hartwig
John H
JH
Stossel
Thomas P
TP
D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D018260:Gelsolin / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D008246:Lysophospholipids / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D019007:P-Selectin / Q000096:biosynthesis; D010972:Platelet Activating Factor / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D015854:Up-Regulation
D018260:Gelsolin; D008246:Lysophospholipids; D009842:Oligopeptides; D019007:P-Selectin; D010972:Platelet Activating Factor; D011994:Recombinant Proteins; D013481:Superoxides; C032881:lysophosphatidic acid