title: Isoflurane prevents acute lung injury through ADP-mediated platelet inhibition.
abstract: BACKGROUND
  Growing evidence suggests platelets are essential in posttraumatic, acute lung injury (ALI). Halogenated ethers interfere with the formation of platelet-granulocyte aggregates. The potential benefit of halogenated ethers has not been investigated in models of trauma/hemorrhagic shock (T/HS). Therefore, we hypothesized that isoflurane decreases T/HS-mediated ALI through platelet inhibition.
  
  
  METHODS
  Sprague-Dawley rats (n = 47) were anesthetized by either pentobarbital or inhaled isoflurane and placed into (1) control, (2) trauma (laparotomy) sham shock, (3) T/HS (mean arterial pressure, 30 mmHg × 45 min), (4) pretreatment with an ADP receptor antagonist, or (5) T/HS with isoflurane initiated during resuscitation groups. ALI was determined by protein and pulmonary immunofluorescence bronchoalveolar lavage (BAL) fluid. Platelet Mapping specifically evaluated thrombin-independent inhibition of the ADP and AA pathways of platelet activation.
  
  
  RESULTS
  Pretreatment with isoflurane abrogated ALI as measured by both BAL fluid protein and pulmonary immunofluorescence (P < .001). Platelet Mapping revealed specific inhibition of the platelet ADP-pathway with isoflurane (P < .001). Pretreatment with an ADP receptor antagonist decreased ALI to sham levels, confirming that specific platelet ADP inhibition decreases ALI. Isoflurane initiated during resuscitation also decreased ALI (P < .001).
  
  
  CONCLUSIONS
  Isoflurane attenuates ALI through an antiplatelet mechanism, in part, through inhibition of the platelet ADP pathway. Isoflurane given postinjury also protects against ALI, and highlights the potential applications of this therapy in various clinical scenarios of ischemia/reperfusion.
authors: Department of Surgery, University of Colorado Denver, Aurora, CO, USA.
authors: Jeffrey N
authors: JN
authors: Harr
authors: Ernest E
authors: EE
authors: Moore
authors: John
authors: J
authors: Stringham
authors: Max V
authors: MV
authors: Wohlauer
authors: Miguel
authors: M
authors: Fragoso
authors: Wilbert L
authors: WL
authors: Jones
authors: Fabia
authors: F
authors: Gamboni
authors: Christopher C
authors: CC
authors: Silliman
authors: Anirban
authors: A
authors: Banerjee
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology / Q000517:prevention & control*; D018685:Anesthetics, Inhalation / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects*; D000077144:Clopidogrel; D005455:Fluorescent Antibody Technique; D007530:Isoflurane / Q000494:pharmacology* / Q000627:therapeutic use; D008168:Lung / Q000473:pathology; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000150:complications; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D018685:Anesthetics, Inhalation; C553058:P2ry12 protein, rat; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D000077144:Clopidogrel; D007530:Isoflurane; D013988:Ticlopidine