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(Stroke. 2001;32:544.)
© 2001 American Heart Association, Inc.

Original Contributions

Reduction of Inflammatory Response in the Mouse Brain With Adenoviral-Mediated Transforming Growth Factor-ß1 Expression

Li Pang, MD; Wen Ye, MD; Xiao-Ming Che, MD; Blake J. Roessler, MD; A. Lorris Betz, MD, PhD Guo-Yuan Yang, MD, PhD

From the Departments of Surgery (L.P., W.Y., X-M.C., A.L.B., G-Y.Y.) and Internal Medicine (B.J.R.), Medical School, University of Michigan, Ann Arbor; Institute of Neurology, Hua-Shan Hospital, Shanghai Medical University (People’s Republic of China) (L.P., X-M.C.); and Departments of Pediatrics, Neurology, and Anatomy, Medical School, University of Utah, Salt Lake City (A.L.B.).

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-1 (MIP-1), 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-1, 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-1 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-1, 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-1 expressed in the ischemic region may play an important role in attracting inflammatory cells. The reduction of MCP-1 and MIP-1, 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.

Key Words: cerebral ischemia, focal • cytokine • gene therapy • inflammation • mice

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