Tissue-destructive macrophages in giant cell arteritis

Giant cell arteritis (GCA) is an inflammatory vasculopathy in which T cells and macrophages infiltrate the wall of medium and large arteries. Clinical consequences such as blindness and stroke are related to arterial occlusio n: Formation of aortic aneurysms may result from necrosis of smooth muscle cells and fragmentation of elastic membranes; The molecular mechanisms of a rterial wall injury in GCA are not understood. To identify mechanisms of ar terial damage gene expression in inflamed and unaffected temporal artery sp ecimens was compared by differential display polymerase chain reaction. Gen es differentially expressed in arterial: lesions included 3 products encode d by the mitochondrial genome. Immunohistochemistry with antibodies specifi c for a 65-kDa mitochondrial antigen revealed that increased expression of mitochondrial products was characteristic of multinucleated giant cells and of CD68+ macrophages that cluster in the media and at the media-intima jun ction. 4-Hydroxy-2-nonenal adducts, products of lipid peroxidation, were de tected on smooth muscle cells and on tissue infiltrating cells, in close pr oximity to multinucleated giant cells and CD68+ macrophages. Also, giant ce lls and macrophages with overexpression of mitochondrial products were able to synthesize metalloproteinase-2. Our data suggest that in the vascular l esions characteristic for GCA, a subset of macrophages has the potential to support several pathways of arterial injury, including the release of reac tive oxygen species and the production of metalloproteinase-2. This macroph age subset is topographically defined and is also identified by overexpress ion of mitochondrial genes. Because these macrophages have a high potential to promote several mechanisms of arterial wall damage, they should be ther apeutically targeted to prevent blood vessel destruction.