title: Minocycline and doxycycline, but not tetracycline, mitigate liver and kidney injury after hemorrhagic shock/resuscitation.
abstract: BACKGROUND
  Despite recovery of hemodynamics by fluid resuscitation after hemorrhage, development of the systemic inflammatory response and multiple organ dysfunction syndromes can nonetheless lead to death. Minocycline and doxycycline are tetracycline derivatives that are protective in models of hypoxic, ischemic, and oxidative stress. Our aim was to determine whether minocycline and doxycycline protect liver and kidney and improve survival in a mouse model of hemorrhagic shock and resuscitation.
  
  
  METHODS
  Mice were hemorrhaged to 30 mmHg for 3 h and then resuscitated with shed blood followed by half the shed volume of lactated Ringer's solution containing tetracycline (10 mg/kg), minocycline (10 mg/kg), doxycycline (5 mg/kg), or vehicle. For pretreatment plus posttreatment, drugs were administered intraperitoneally prior to hemorrhage followed by second equal dose in Ringer's solution after blood resuscitation. Blood and tissue were harvested after 6 h.
  
  
  RESULTS
  Serum alanine aminotransferase (ALT) increased to 1,988 and 1,878 U/L after posttreatment with vehicle and tetracycline, respectively, whereas minocycline and doxycycline posttreatment decreased ALT to 857 and 863 U/L. Pretreatment plus posttreatment with minocycline and doxycycline also decreased ALT to 849 and 834 U/L. After vehicle, blood creatinine increased to 134 µM, which minocycline and doxycycline posttreatment decreased to 59 and 56 µM. Minocycline and doxycycline pretreatment plus posttreatment decreased creatinine similarly. Minocycline and doxycycline also decreased necrosis and apoptosis in liver and apoptosis in both liver and kidney, the latter assessed by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) and caspase 3 activation. Lastly after 4.5 h of hemorrhage followed by resuscitation, minocycline and doxycycline (but not tetracycline) posttreatment improved 1-week survival from 38% (vehicle) to 69% and 67%, respectively.
  
  
  CONCLUSIONS
  Minocycline and doxycycline were similarly protective when given before as after blood resuscitation and might therefore have clinical efficacy to mitigate liver and kidney injury after resuscitated hemorrhage.
authors: *Center for Cell Death, Injury & Regeneration, Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC; †Department of Trauma Surgery, J.W. Goethe University, Frankfurt am Main, Germany; and ‡Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC; and §Institute of Theoretical & Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russian Federation.
authors: Andaleb
authors: A
authors: Kholmukhamedov
authors: Christoph
authors: C
authors: Czerny
authors: Jiangting
authors: J
authors: Hu
authors: Justin
authors: J
authors: Schwartz
authors: Zhi
authors: Z
authors: Zhong
authors: John J
authors: JJ
authors: Lemasters
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000097:blood; D053148:Caspase 3 / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D019610:Cytoprotection; D004195:Disease Models, Animal; D004318:Doxycycline / Q000008:administration & dosage*; D005440:Fluid Therapy; D006439:Hemodynamics; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008911:Minocycline / Q000008:administration & dosage*; D009102:Multiple Organ Failure / Q000097:blood / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009336:Necrosis; D020011:Protective Agents / Q000008:administration & dosage*; D012151:Resuscitation / Q000379:methods*; D012771:Shock, Hemorrhagic / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D013752:Tetracycline / Q000008:administration & dosage*; D013997:Time Factors
chemical_list: D015415:Biomarkers; D020011:Protective Agents; D003404:Creatinine; D000410:Alanine Transaminase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D013752:Tetracycline; D008911:Minocycline; D004318:Doxycycline