title: Reduction of inflammatory response in the mouse brain with adenoviral-mediated transforming growth factor-ss1 expression.
abstract: Background and Purpose-Chemokines have been shown to play an important role in leukocyte and monocyte/macrophage infiltration into ischemic regions. The purpose of this study is to identify whether overexpression of the active human transforming growth factor-ss1 (ahTGF-ss1) can downregulate expression of monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1alpha (MIP-1alpha), and intercellular adhesion molecule-1 (ICAM-1) and reduce ischemic brain injury.
  
  
  METHODS
  -Overexpression of transforming growth factor-ss1 (TGF-ss1) was achieved through adenoviral gene transfer. Five days after adenoviral transduction, the mouse underwent 30 minutes of middle cerebral artery occlusion followed by 1 to 7 days of reperfusion. TGF-ss1, MCP-1, MIP-1alpha, and ICAM-1 were detected by enzyme-linked immunosorbent assay and immunohistochemistry. Infarct areas and volumes were measured by cresyl violet staining.
  
  
  RESULTS
  -MCP-1 and MIP-1alpha expression is increased after middle cerebral artery occlusion, and double-labeled immunostaining revealed that MCP-1 is colocalized with neurons and astrocytes. Viral-mediated TGF-ss1 overexpression was significantly greater at measured time points, with a peak at 7 to 9 days. The expression of MCP-1 and MIP-1alpha, but not ICAM-1, was reduced in the mice overexpressing ahTGF-ss1 (P:<0.05). Furthermore, infarct volume was significantly reduced in the mice overexpressing ahTGF-ss1 (P:<0.05).
  
  
  CONCLUSIONS
  -This study demonstrates that MCP-1 and MIP-1alpha expressed in the ischemic region may play an important role in attracting inflammatory cells. The reduction of MCP-1 and MIP-1alpha, but not ICAM-1, in the mice overexpressing ahTGF-ss1 suggests that the neuroprotective effect of TGF-ss1 may result from the inhibition of chemokines during cerebral ischemia and reperfusion.
authors.affiliation: Department of Surgery, Medical School, University of Michigan, Ann Arbor, MI 48109-0532, USA.
authors.forename: L
authors.initials: L
authors.lastname: Pang
authors.forename: W
authors.initials: W
authors.lastname: Ye
authors.forename: X M
authors.initials: XM
authors.lastname: Che
authors.forename: B J
authors.initials: BJ
authors.lastname: Roessler
authors.forename: A L
authors.initials: AL
authors.lastname: Betz
authors.forename: G Y
authors.initials: GY
authors.lastname: Yang
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001783:Blood Flow Velocity; D001921:Brain / Q000098:blood supply / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D002545:Brain Ischemia / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018932:Chemokine CCL2 / Q000378:metabolism; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D051379:Mice; D015424:Reperfusion; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
chemical_list: D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D018799:Intercellular Adhesion Molecule-1