Hypertonic saline up-regulates A3 adenosine receptor expression of activated neutrophils and increases acute lung injury after sepsis

Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Critical care medicine (Impact Factor: 6.15). 10/2008; 36(9):2569-75. DOI: 10.1097/CCM.0b013e3181841a91
Source: PubMed

ABSTRACT Hypertonic saline resuscitation reduces tissue damage by inhibiting polymorphonuclear neutrophils. Hypertonic saline triggers polymorphonuclear neutrophils to release adenosine triphosphate that is converted to adenosine, inhibiting polymorphonuclear neutrophils through A2a adenosine receptors. Polymorphonuclear neutrophils also express A3 adenosine receptors that enhance polymorphonuclear neutrophil functions. Here we investigated whether A3 receptors may diminish the efficacy of hypertonic saline in a mouse model of acute lung injury.
Randomized animal study and laboratory investigation.
University research laboratory.
The effect of A3 receptors on the efficacy of hypertonic saline resuscitation was assessed in A3 receptor knockout and wild-type mice. Animals were treated with hypertonic saline (7.5% NaCl, 4 mL/kg) before or after cecal ligation and puncture, and acute lung injury and mortality were determined. The effect of timing of hypertonic saline exposure on A3 receptor expression and degranulation was studied in vitro with isolated human polymorphonuclear neutrophils.
Treatment of human polymorphonuclear neutrophils with hypertonic saline before stimulation with formyl methionyl-leucyl-phenylalanine inhibited A3 receptor expression and degranulation, whereas hypertonic saline-treatment after formyl methionyl-leucyl-phenylalanine-stimulation augmented A3 receptor expression and degranulation. Acute lung injury in wild-type mice treated with hypertonic saline after cecal ligation and puncture was significantly greater than in wild-type mice pretreated with hypertonic saline. This aggravating effect of delayed hypertonic saline-treatment was absent in A3 receptor knockout mice. Similarly, mortality in wild-type mice with delayed hypertonic saline-treatment was significantly higher (88%) than in animals treated with hypertonic saline before cecal ligation and puncture (50%). Mortality in A3 receptor knockout mice remained only 50% regardless of timing of hypertonic saline administration.
Polymorphonuclear neutrophil A3 receptors expression determines whether hypertonic saline resuscitation inhibits or aggravates polymorphonuclear neutrophil-induced acute lung injury. These findings suggest that A3 antagonists could improve the efficacy of hypertonic saline resuscitation by reducing side effects in patients whose polymorphonuclear neutrophils are activated before hypertonic saline treatment.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This review article provides a historical perspective on the role of purinergic signalling in the regulation of various subsets of immune cells from early discoveries to current understanding. It is now recognised that adenosine 5'-triphosphate (ATP) and other nucleotides are released from cells following stress or injury. They can act on virtually all subsets of immune cells through a spectrum of P2X ligand-gated ion channels and G protein-coupled P2Y receptors. Furthermore, ATP is rapidly degraded into adenosine by ectonucleotidases such as CD39 and CD73, and adenosine exerts additional regulatory effects through its own receptors. The resulting effect ranges from stimulation to tolerance depending on the amount and time courses of nucleotides released, and the balance between ATP and adenosine. This review identifies the various receptors involved in the different subsets of immune cells and their effects on the function of these cells.
    Purinergic Signalling 10/2014; DOI:10.1007/s11302-014-9427-2 · 3.51 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This study compared the effect of hydroxyethyl starch 130/0.4, hydroxyethyl starch 200/0.5, and succinylated gelatin on oxidative stress and the inflammatory response in a rodent hemorrhagic shock model. Sodium pentobarbital-anesthetized adult male Wistar rats (200 g - 220 g) were subjected to a severe volume-controlled hemorrhage using arterial blood withdrawal (30 mL/kg - 33 mL/kg), and resuscitated with a colloid solution at the same volume as blood withdrawal (hydroxyethyl starch 130/0.4, hydroxyethyl starch 200/0.5, or succinylated gelatin). Arterial blood gas parameters were monitored. Malondialdehyde (MDA) content, myeloperoxidase (MPO) activity in the liver, lungs, intestine, and brain were measured 2 hours after resuscitation. The levels of tumor necrosis factor (TNF)- alpha and interleukin (IL)-6 in the intestine were also measured. Infusions of hydroxyethyl starch 130/0.4, but not hydroxyethyl starch 200/0.5 or succinylated gelatin, significantly reduced MDA levels and MPO activity in the liver, intestine, lungs, and brain, and it also inhibited the production of TNF-alpha in the intestine 2 hours after resuscitation. However, no significant difference between hydroxyethyl starch 200/0.5 and succinylated gelatin was observed. Hydroxyethyl starch 130/0.4, but not hydroxyethyl starch 200/0.5 and succinylated gelatin, treatment after hemorrhagic shock ameliorated oxidative stress and the inflammatory response in this rat model. No significant differences were observed after hydroxyethyl starch 200/0.5 and succinylated gelatin administration at doses of approximately 33 mL/kg.
    Critical care (London, England) 07/2013; 17(4):R141. DOI:10.1186/cc12820 · 5.04 Impact Factor
    This article is viewable in ResearchGate's enriched format
  • [Show abstract] [Hide abstract]
    ABSTRACT: Activation of polymorphonuclear neutrophils (PMN) is thought to contribute to traumatic brain injury (TBI). Because hypertonic fluids can inhibit PMN activation, we studied whether hypertonic fluid resuscitation can reduce PMN activation in TBI patients. Trauma patients with severe TBI were resuscitated with 250 ml of either 7.5% hypertonic saline (HS; n=22), HS + 6% dextran-70 (HSD; n=22), or 0.9% normal saline (NS; n=39) and blood samples were collected on hospital admission and 12 and 24 h after resuscitation. PMN activation (CD11b, CD62L, CD64) and degranulation (CD63, CD66b, CD35) markers and oxidative-burst activity as well as spontaneous PMN apoptosis were measured by flow cytometry. Relative to healthy controls, TBI patients showed increased PMN activation and decreased apoptosis of PMN. In the HS group, but not in the HSD group, markers of PMN adhesion (CD11b, CD64) and degranulation (CD35, CD66b) were significantly lower than in the NS group. These effects were particularly pronounced 12 h after resuscitation. Treatment with HS and HSD inhibited PMN oxidative burst responses compared to NS-treated patients. HS alone partially restored apoptosis. Despite these differences, the groups did not differ in clinical outcome parameters such as mortality and Extended Glasgow Outcome Scale. This study demonstrates that pre-hospital resuscitation with HS can partially restore normal PMN activity and the apoptotic behavior or PMNs, while resuscitation with HSD was largely ineffective. Although the results are intriguing, additional research will be required to translate these effects of HS into treatment strategies that improve clinical outcome in TBI patients.
    Shock (Augusta, Ga.) 10/2013; DOI:10.1097/SHK.0000000000000038 · 2.87 Impact Factor


1 Download
Available from