No abstract

No abstract

Wirth, Delphine, Fabrice Bureau, Dorothée Melotte, Elisabeth Christians, and Pascal Gustin. Evidence for a role of heat shock factor 1 in inhibition of NF-B pathway during heat shock responsemediated lung protection. Am J Physiol Lung Cell Mol Physiol 287: L953-L961, 2004. First published June 25, 2004 doi:10.1152/ ajplung.00184.2003.-Heat shock transcription factor (HSF)-1 is recognized as a central component of the heat shock response, which protects against various harmful conditions. However, the mechanisms underlying the protection and the role of HSF-1 in these mechanisms have not yet been clearly elucidated. Using HSF-1 knockout mice (Hsf1 Ϫ/Ϫ ), we examined whether heat shock responsemediated lung protection involved an inhibition of the proinflammatory pathway via an interaction between HSF-1 and NF-B, in response to cadmium insult. The HSF-1-dependent protective effect against intranasal instillation of cadmium (10 and 100 g/mouse) was demonstrated by the higher protein content (1.2-and 1.4-fold), macrophage (1.6-and 1.9-fold), and neutrophil (2.6-and 1.8-fold) number in bronchoalveolar fluids, higher lung wet-to-dry weight ratio, and more severe lung damage evaluated by histopathology in Hsf1 Ϫ/Ϫ compared with wild-type animals. These responses were associated with higher granulocyte/macrophage colony-stimulating factor (GM-CSF; 1.7-fold) but not TNF-␣ concentrations in bronchoalveolar fluids of Hsf1 Ϫ/Ϫ mice compared with those of wild-type animals, indicating that HSF-1 behaved as a repressor of specific cytokine production in our model. To further investigate the mechanism of GM-CSF repression, we analyzed the NF-B activity and IB stability. The DNA binding NF-B activity, in particular p50 homodimer activity, was higher in Hsf1 Ϫ/Ϫ mice than in wild-type mice after cadmium exposure. These results provide a first line of evidence that mechanisms of lung protection depending on HSF-1 involve specific cytokine repression via inhibition of NF-B activation in vivo. knockout mice; cadmium; heat shock proteins; granulocyte/macrophage colony-stimulating factor; nuclear factor-B

Members of heat shock proteins (Hsp70) family have been considered to respond to a large variety of stressful conditions. But it was suggested that, in pulmonary cells, Hsp response depends more closely on the type of stimulus. The lungs are critical organs potentially subjected to air pollution affecting respiratory function and, therefore, these organs are of particular interest with regard to the stress response. To investigate the stress dependence of Hsp70 response in lungs, we created transgenic mice where the firefly luciferase reporter gene is under the control of the murine hsp70-1 promoter and exposed them to different sublethal toxic conditions. For each condition, the level of transgene induction and pulmonary toxicity were assessed. We found that hsp70-1 promoter was stimulated by heat shock and cadmium but not by ozone, paraquat, and parathion, even if these chemicals induced respiratory distress and lung inflammation. Similar observations were made when expression of the endogenous hsp70-1 gene was analyzed, indicating that our transgenic model was accurately detecting hsp70-1 induction. Thereby, it appeared that hsp70-1 response is selective and depends on signaling pathways triggered by the toxicants rather than by their pathologic toxicity per se. Furthermore, because all the chemicals used in our study have been previously described to increase the level of oxidative stress, it indicates that there is no direct and simple correlation between hsp70-1 response and the level of oxidative stress, but more specific oxidative patterns should be involved in Hsp regulation.

No abstract