title: Hypertonic saline enhances neutrophil elastase release through activation of P2 and A3 receptors.
abstract: Hypertonic saline (HS) holds promise as a novel resuscitation fluid for the treatment of trauma patients because HS inhibits polymorphonuclear neutrophil (PMN) activation and thereby prevents host tissue damage and associated posttraumatic complications. However, depending on conditions of cell activation, HS can increase PMN degranulation, which could exacerbate tissue damage in trauma victims. The cellular mechanism by which HS increases degranulation is unknown. In the present study, we tested whether HS-induced ATP release from PMN and feedback via P1 and/or P2 receptors may be involved in the enhancement of degranulation by HS. We found that HS enhances elastase release and ERK and p38 MAPK activation when HS is added after activation of PMN with formyl peptide (fMLP) or phorbol ester (PMA). Agonists of P2 nucleotide and A3 adenosine receptors mimicked these enhancing effects of HS, whereas antagonists of A3 receptors or removal of extracellular ATP with apyrase diminished the response to HS. A1 adenosine receptor antagonists increased the enhancing effect of HS, whereas A1 receptor agonists inhibited elastase release. These data suggest that HS upregulates degranulation via ATP release and positive feedback through P2 and A3 receptors. We propose that these feedback mechanisms can serve as potential pharmacological targets to fine-tune the clinical effectiveness of HS resuscitation.
authors.affiliation: Surgical Immunology Research Laboratory, Department of Surgery, Division of Trauma, University of California San Diego Medical Center, 200 West Arbor Dr., 92103-8236, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Hashiguchi
authors.forename: Linda
authors.initials: L
authors.lastname: Yip
authors.forename: Wolfgang G
authors.initials: WG
authors.lastname: Junger
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D025461:Feedback, Physiological; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D012462:Saline Solution, Hypertonic / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D043682:Receptor, Adenosine A1; D043684:Receptor, Adenosine A3; D018048:Receptors, Purinergic P2; D012462:Saline Solution, Hypertonic; D009240:N-Formylmethionine Leucyl-Phenylalanine; D000255:Adenosine Triphosphate; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019272:Leukocyte Elastase; D013755:Tetradecanoylphorbol Acetate