Transforming growth factor-␤ 1 (TGF-␤ 1 ) induces ␣-smooth muscle actin (␣-SMA) and collagen synthesis in fibroblast both in vivo and in vitro and plays a significant role in tissue repair and the development of fibrosis. During these processes the fibroblasts differentiate into activated fibroblasts (so called myofibroblasts), characterized by increased ␣-SMA expression. Because TGF-␤ 1 is considered the main inducer of the myofibroblast phenotype and cytoskeletal changes accompany this differentiation, the main objective of this investigation was to study how TGF-␤ 1 alters protein expression of cytoskeletal-associated proteins. Metabolic labeling of cell cultures by [ 35 S]methionine, followed by protein separation on twodimensional gel electrophoresis, displayed ϳ2500 proteins in the pI interval of 3-10. Treatment of TGF-␤ 1 led to specific spot pattern changes that were identified by mass spectrometry and represent specific induction of several members of the contractile apparatus such as calgizzarin, cofilin, and profilin. These proteins have not previously been shown to be regulated by TGF-␤ 1 , and the functional role of these proteins is to participate in the depolymerization and stabilization of the microfilaments. These results show that TGF-␤ 1 induces not only ␣-SMA but a whole set of actin-associated proteins that may contribute to the increased contractile properties of the myofibroblast. These proteins accompany the induced expression of ␣-SMA and may participate in the formation of stress fibers, cell contractility, and cell spreading characterizing the myofibroblasts phenotype.

No abstract

1. The pharmacokinetics of the two enantiomers of terbutaline, (+)T and (‐)T, and the racemate (+/‐)T, have been evaluated after single intravenous and oral dosage to six healthy volunteers. 2. The mean systemic clearance, CL, was 0.19 and 0.13 l h‐1 kg‐1 for (+)T and (‐)T, respectively. This difference was statistically significant. The mean clearance of (+/‐)T was 0.20 l h‐1 kg‐1. Volumes of distribution were similar (1.9 l kg‐1) after the three intravenous administrations. The differences in CL were reflected in values of the elimination half‐life and MRT. 3. The difference in CL of the isomers could be explained by a corresponding difference in their renal clearance, CLR. Competition for stereoselective active reabsorption in the tubule might explain why (+)T seemed to enhance the CLR of (‐)T when the drug was given as the racemate. 4. Oral bioavailability, calculated from plasma data, of (+)T was 7.5% and that of (‐)T was 14.8%. This difference was statistically significant and was mainly due to a difference in absorption of (+)T and (‐)T, but also to a difference in their subsequent first‐pass metabolism. The bioavailability of (+/‐)T was similar to that of (‐)T. 5. (‐)T appears to govern the absorption properties of the racemate, while (+)T determines its elimination behaviour. Systemic metabolism of the two enantiomers was similar and, therefore, a greater first‐pass metabolism of (+)T would reflect a higher capacity of the gut wall to metabolise this isomer.

We conclude that a single IVMP treatment is efficacious and safe in the treatment of moderate MG.