Changes that may occur in the expression of protein and mRNA for TGF-beta isoforms in response to various disease states and tissue treatments are being investigated using immunohistochemistry and Northern blot techniques. For example, we have found that there are changes in expression of TGF-beta protein in the mouse brain during experimental allergic encephalomyelitis. In mouse embryos, changes in the localization of protein occur following retinoic acid treatment, while ovarian steroids alter expression of TGF-betas in the mouse uterus. Following heat shock of rats, there are transient increases in TGF-betas in the heart which may mediate the cardioprotective effects of heat shock. This hypothesis is being investigated by measuring recovery of contractile force following ischemia-reperfusion in an isolated perfused heart system. This is being done in hearts from rats exposed to heat shock, as well as in control animals in the presence or absence of TGF-beta or TGF-beta antibodies. Similar changes in TGF-beta expression occur in cultured cardiac cells following heat shock. TGF-beta also can induce its own expression in these cell types. The actions of TGF-beta in the heart during septic shock are also being investigated. Lipopolysaccharide (LPS) treatment of rats causes destruction of the collagen ultrastructure of the heart as determined by scanning electron microscopy and the ability of TGF-beta to reduce the molecular defect is being examined. LPS treatment of cultured cardiac myocytes induces expression of collagenase mRNA and this induction is abolished by TGF-beta. TGF-beta expression in hearts of dogs treated with tumor necrosis factor-alpha, which reduces cardiac output, is also being examined.
