title: Cardiopulmonary bypass during cardiac surgery modulates systemic inflammation by affecting different steps of the leukocyte recruitment cascade.
abstract: BACKGROUND
  It is known that the use of a cardiopulmonary bypass (CPB) during cardiac surgery leads to leukocyte activation and may, among other causes, induce organ dysfunction due to increased leukocyte recruitment into different organs. Leukocyte extravasation occurs in a cascade-like fashion, including capturing, rolling, adhesion, and transmigration. However, the molecular mechanisms of increased leukocyte recruitment caused by CPB are not known. This clinical study was undertaken in order to investigate which steps of the leukocyte recruitment cascade are affected by the systemic inflammation during CPB.
  
  
  METHODS
  We investigated the effects of CPB on the different steps of the leukocyte recruitment cascade in whole blood from healthy volunteers (n = 9) and patients undergoing cardiac surgery with the use of cardiopulmonary bypass (n = 7) or in off-pump coronary artery bypass-technique (OPCAB, n = 9) by using flow chamber experiments, transmigration assays, and biochemical analysis.
  
  
  RESULTS
  CPB abrogated selectin-induced slow leukocyte rolling on E-selectin/ICAM-1 and P-selectin/ICAM-1. In contrast, chemokine-induced arrest and transmigration was significantly increased by CPB. Mechanistically, the abolishment of slow leukocyte rolling was due to disturbances in intracellular signaling with reduced phosphorylation of phospholipase C (PLC) γ2, Akt, and p38 MAP kinase. Furthermore, CPB induced an elevated transmigration which was caused by upregulation of Mac-1 on neutrophils.
  
  
  CONCLUSIONS
  These data suggest that CPB abrogates selectin-mediated slow leukocyte rolling by disturbing intracellular signaling, but that the clinically observed increased leukocyte recruitment caused by CPB is due to increased chemokine-induced arrest and transmigration. A better understanding of the underlying molecular mechanisms causing systemic inflammation after CPB may aid in the development of new therapeutic approaches.
authors.affiliation: Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Rossaint
authors.forename: Christian
authors.initials: C
authors.lastname: Berger
authors.forename: Hugo
authors.initials: H
authors.lastname: Van Aken
authors.forename: Hans H
authors.initials: HH
authors.lastname: Scheld
authors.forename: Peter K
authors.initials: PK
authors.lastname: Zahn
authors.forename: Andreas
authors.initials: A
authors.lastname: Rukosujew
authors.forename: Alexander
authors.initials: A
authors.lastname: Zarbock
mesh_terms: D000368:Aged; D002469:Cell Separation; D001026:Coronary Artery Bypass; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007962:Leukocytes / Q000276:immunology*; D008297:Male; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology*
chemical_list: D011494:Protein Kinases; D051966:Phospholipase C gamma