title: SIRT1 mediates a primed response to immune challenge after traumatic lung injury.
abstract: BACKGROUND
  Pulmonary contusion (PC) is a common, potentially lethal injury that results in priming for exaggerated inflammatory responses to subsequent immune challenge like infection (second hit). The molecular mechanism of priming and the second hit phenomenon after PC remain obscure. With the use of a mouse model of PC, this study explores the role of sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, in priming for a second hit after injury.
  
  
  METHODS
  With the use of a mouse model of PC, injury-primed second-hit host responses were tested at 24 hours after PC by (1) in vivo infectious challenge of injured mice or (2) ex vivo inflammatory challenge of isolated immune cells from injured mice. SIRT activators or repressors were used to test for SIRT1 participation in these second-hit responses.
  
  
  RESULTS
  PC-injured mice given an in vivo infectious challenge by cecal ligation and puncture (CLP) had significantly increased mortality compared with injury or infectious challenge alone. Isolated bronchoalveolar lavage (BAL) cells from injured mice given an ex vivo inflammatory challenge with bacterial lipopolysaccharide (LPS) had increased levels of tumor necrosis factor α messenger RNA compared with uninjured mice. We found that PC reduced SIRT1 protein, messenger RNA, and SIRT1 enzymatic activity in injured lung tissue. We also found decreased SIRT1 protein levels in BAL cells from injured mice. We further found that injured mice treated with a SIRT1 activator, resveratrol, showed significantly decreased polymorphonuclear leukocytes (PMN) in the BAL in response to intratracheal LPS and increased survival from CLP.
  
  
  CONCLUSIONS
  These results showed that PC decreased SIRT1 levels in the lung correlated with enhanced responses to infectious or inflammatory stimuli in injured mice. Treatment of injured mice with a SIRT1 activator, resveratrol, decreased LPS inflammatory response and increased survival after CLP. Our results suggest that SIRT1 participates in the second-hit response after injury.
authors.affiliation: From the Departments of Emergency Medicine (L.M.S.), General Surgery (J.J.H., J.D.W., B.K.Y.), and Anesthesiology/Critical Care (V.T.V.), and Section on Molecular Medicine (C.E.M.), Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Lane M
authors.initials: LM
authors.lastname: Smith
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Wells
authors.forename: Vidula T
authors.initials: VT
authors.lastname: Vachharajani
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Yoza
authors.forename: Charles E
authors.initials: CE
authors.lastname: McCall
authors.forename: J Jason
authors.initials: JJ
authors.lastname: Hoth
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007111:Immunity, Cellular / Q000187:drug effects / Q000235:genetics*; D015151:Immunoblotting; D007150:Immunohistochemistry; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics*; D000077185:Resveratrol; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors; D056564:Sirtuin 1 / Q000096:biosynthesis / Q000235:genetics*; D013267:Stilbenes / Q000494:pharmacology
chemical_list: D012333:RNA, Messenger; D013267:Stilbenes; D012264:Ribonucleotide Reductases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000077185:Resveratrol