The Molecular Mechanisms of Thalidomide Teratogenicity and Implications for Modern Medicine.

Thalidomide is a teratogen that affects many organs but primarily induces limb truncations like phocomelia. Rodents are thalidomide resistant. In the 1950s, this has led to misinterpretations of animal tests and to the fatal assumption that the drug was safe for pregnant women to use against morning sickness. The result was one of the biggest scandals in medical history: 10.000 and more infants with birth defects in Europe. Nonetheless, thalidomide still has its place in modern medicine as it has strong therapeutic potential: it has been approved by the FDA for multiple myeloma and erythema nodosum leprosum, and its anti-inflammatory, immunomodulatory and antiangiogenic activities are considered in many other refractory diseases. The aim is to develop derivatives that are not teratogenic but maintain the therapeutic potential. This requires detailed knowledge about the underlying molecular mechanisms. Much progress has been made in deciphering the teratogenic mechanisms in the last decade. Here, we summarize these mechanisms, explain thalidomide resistance of rodents, and discuss possible mechanisms that could explain why the drug primarily targets the developing limb in the embryo. We also summarize the most important therapeutic mechanisms. Finally, we discuss which therapeutic and teratogenic mechanisms do and do not overlap, and if there is a chance for the development of non-teratogenic thalidomide derivatives with therapeutic potential.

TNFalpha-induced GM-CSF release from human airway smooth muscle cells depends on activation of an ET-1 autoregulatory positive feedback mechanism.

BACKGROUND: There is an urgent need to inhibit endothelin-1 (ET-1) induced chronic inflammatory processes in early stages of lung diseases in order to prevent untreatable irreversible stages often accompanied by lung fibrosis and pulmonary hypertension. Nothing is known about the airway inflammation-inducing and/or maintaining role of ET-1 in human airway smooth muscle cells (HASMCs). OBJECTIVE: ET-1 and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression in response to tumour necrosis factor alpha (TNFalpha) and ET-1 stimulation was investigated, and the impact of mitogen-activated protein kinase (MAPK) pathways in this context was studied. To elucidate the anti-inflammatory properties of the dual endothelin receptor antagonist bosentan that targets both endothelin receptor subtypes A (ET(A)R) and B (ET(B)R), its effect on the TNFalpha/ET-1/GM-CSF network was investigated. METHODS: ET-1 and GM-CSF expression and activation of MAPKs were investigated via quantitative reverse transcription-PCR (RT-PCR), western blotting and ELISA. MAIN RESULTS: Both TNFalpha and ET-1 activated p38(MAPK) and extracellular signal-regulated kinase (ERK)-1/-2 signalling. ET-1 expression was induced by TNFalpha and by ET-1 itself. Both effects were inhibited by bosentan and by specific ET(A)R or p38(MAPK) blockade. ET-1- and TNFalpha-induced GM-CSF expression were both reduced by bosentan as well as by specific inhibition of either ET(A)R, ET(B)R, p38(MAPK) or ERK-1/-2. CONCLUSION: TNFalpha activates an ET(A)R- and p38(MAPK)-dependent ET-1 autoregulatory positive feedback loop to maintain GM-CSF release from HASMCs. Since bosentan impairs ET-1 autoregulation and TNFalpha-induced ET-1 release, as well as TNFalpha- and ET-1-induced GM-CSF release, the present data suggest therapeutic utility for bosentan in treating particularly the early stages of chronic inflammatory airway diseases.