title: Influenza virus infection aggravates stroke outcome.
abstract: OBJECTIVE
  Stroke is triggered by several risk factors, including influenza and other respiratory tract infections. However, it is unknown how and in which way influenza infection affects stroke outcome.
  
  
  METHODS
  We infected mice intranasally with human influenza A (H1N1) virus and occluded the middle cerebral artery to induce ischemic strokes. Infarct volume and intracerebral hemorrhage were determined by histology. To evaluate the integrity of the blood-brain barrier and inflammation, we measured various cytokines in vivo and in vitro and performed immunohistochemistry of leukocyte markers, collagen IV, immunoglobulins, and matrix metalloproteinase-9.
  
  
  RESULTS
  Influenza virus infection increased infarct size. Whereas changes in cardiovascular parameters did not explain this effect, we found evidence for an inflammatory mechanism. In influenza virus infection, the respiratory tract released cytokines into the blood, such as RANTES that induced macrophage inflammatory protein-2 and other inflammatory mediators in the ischemic brain. In infected mice, there was an increased number of neutrophils expressing the matrix metalloproteinase-9 in the ischemic brain. This was accompanied by severe disruption of the blood-brain barrier and an increased rate of intracerebral hemorrhages after tissue plasminogen activator treatment. To investigate the role of cytokines, we blocked cytokine release by using GTS-21, a selective agonist of the α7 nicotinic acetylcholine receptor. GTS-21 ameliorated ischemic brain damage and improved survival.
  
  
  CONCLUSIONS
  Influenza virus infection triggers a cytokine cascade that aggravates ischemic brain damage and increases the risk of intracerebral hemorrhage after tissue plasminogen activator treatment. Blockade of cytokine production by α7 nicotinic acetylcholine receptor agonists is a novel therapeutic option to treat stroke in a proinflammatory context.
authors.affiliation: Department of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors.forename: Sajjad
authors.initials: S
authors.lastname: Muhammad
authors.forename: Emanuel
authors.initials: E
authors.lastname: Haasbach
authors.forename: Maria
authors.initials: M
authors.lastname: Kotchourko
authors.forename: Anne
authors.initials: A
authors.lastname: Strigli
authors.forename: Antje
authors.initials: A
authors.lastname: Krenz
authors.forename: Dirk A
authors.initials: DA
authors.lastname: Ridder
authors.forename: Annette B
authors.initials: AB
authors.lastname: Vogel
authors.forename: Hugo H
authors.initials: HH
authors.lastname: Marti
authors.forename: Yousef
authors.initials: Y
authors.lastname: Al-Abed
authors.forename: Oliver
authors.initials: O
authors.lastname: Planz
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaninger
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology / Q000821:virology; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000378:metabolism / Q000473:pathology; D053118:Influenza A Virus, H1N1 Subtype / Q000472:pathogenicity; D007251:Influenza, Human / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D012307:Risk Factors; D020521:Stroke / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D018946:Chemokine CCL5; D054426:Chemokine CXCL2