title: Intestinal mast cells mediate gut injury and systemic inflammation in a rat model of deep hypothermic circulatory arrest.
abstract: OBJECTIVE
  Cardiac surgery, especially when employing cardiopulmonary bypass and deep hypothermic circulatory arrest, is associated with systemic inflammatory responses that significantly affect morbidity and mortality. Intestinal perfusion abnormalities have been implicated in such responses, but the mechanisms linking local injury and systemic inflammation remain unclear. Intestinal mast cells are specialized immune cells that secrete various preformed effectors in response to cellular stress. We hypothesized that mast cells are activated in a microenvironment shaped by intestinal ischemia/reperfusion, and investigated local and systemic consequences.
  
  
  METHODS
  Rat model of deep hypothermic circulatory arrest.
  
  
  METHODS
  University research laboratory.
  
  
  METHODS
  Twelve- to 14-week-old male Sprague-Dawley rats.
  
  
  METHODS
  Rats were anesthetized and cooled to 16°C to 18°C on cardiopulmonary bypass before instituting deep hypothermic circulatory arrest for 45 minutes. Specimens were harvested following rewarming and 2 hours of recovery.
  
  
  RESULTS
  Significant intestinal barrier disruption was found, together with macro- and microscopic evidence of ischemia/reperfusion injury in ileum and colon, but not in the lungs or kidneys. Immunofluorescence and toluidine blue staining revealed increased numbers of mast cells and their activation in the gut. In animals pretreated with the mast cell stabilizer, cromolyn sodium, mast cell degranulation was blocked, and intestinal morphology and barrier function were preserved following deep hypothermic circulatory arrest. Furthermore, cromolyn sodium treatment was associated with reduced intestinal neutrophil influx and blunted systemic release of proinflammatory cytokines.
  
  
  CONCLUSIONS
  Our data provide primary evidence that intestinal ischemia/reperfusion is a leading pathophysiologic process in a rat model of deep hypothermic circulatory arrest, and that intestinal injury, and local and systemic inflammatory responses are critically dependent on mast cell activation. This identifies intestinal mast cells as central players in deep hypothermic circulatory arrest-associated responses, and opens novel therapeutic possibilities for patients undergoing this procedure.
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA. jorn.karhausen@duke.edu
authors.forename: Jörn
authors.initials: J
authors.lastname: Karhausen
authors.forename: Ma
authors.initials: M
authors.lastname: Qing
authors.forename: Amelia
authors.initials: A
authors.lastname: Gibson
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Moeser
authors.forename: Harald
authors.initials: H
authors.lastname: Griefingholt
authors.forename: Laura P
authors.initials: LP
authors.lastname: Hale
authors.forename: Soman N
authors.initials: SN
authors.lastname: Abraham
authors.forename: G Burkhard
authors.initials: GB
authors.lastname: Mackensen
mesh_terms: D000818:Animals; D002315:Cardiopulmonary Bypass; D050792:Circulatory Arrest, Deep Hypothermia Induced / Q000009:adverse effects; D004195:Disease Models, Animal; D007036:Hypothermia, Induced; D007422:Intestines / Q000098:blood supply*; D008297:Male; D008407:Mast Cells / Q000276:immunology / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology / Q000503:physiopathology*