Use of Hsf1(-/-) mice reveals an essential role for HSF1 to protect lung against cadmium-induced injury.
Cadmium (Cd) is known to activate heat shock (HS) response, which is characterized by overexpression of heat shock proteins (Hsps) under the control of heat shock factor 1 (HSF1). The potential protection provided by the HS response, induced by increasing the body temperature of animals before Cd exposure or by Cd itself, against pathophysiological changes occurring after Cd intranasal instillation (1 to 100 microg/mouse) was examined. HSF1-deficient mice were used to evaluate the role of this factor in lung protection. Cd instillation caused dose- and time-dependent changes in the respiratory pattern measured by plethysmography (Penh), and significant increases in lactate dehydrogenase (LDH) activity as well as macrophage and neutrophil counts in bronchoalveolar lavage fluids. HS preconditioning induced Hsp overexpression and reduced the Penh (-30%), LDH (-25%), and neutrophil (-55%) responses to subsequent administration of the highest Cd doses (50 and 100 microg) in wild-type mice. HSF1 deficiency abolished the HS response and its protective effect. In the absence of preconditioning, Hsf1(-/-) mice exhibited higher values of Penh (+70%) and LDH activity (+42%) compared with wild-type animals when exposed to the lowest Cd doses. Higher macrophage (+80%) and neutrophil counts (+115%) were recorded whatever the dose. Western blot analyses indicated that lung protection might be related to the kinetics of HSF1-dependent Hsp70 expression. Altogether, our data demonstrate that HS response elicited both by prior HS and by Cd itself moderates pulmonary injuries due to Cd instillation, and that HSF1 is a major mediator in this protection.
Wirth
Delphine
D
Unit of Pharmacology, Pharmacotherapy and Toxicology; Department of Functional Sciences, Faculty of Veterinary Medicine, University of Liege, Belgium.
Christians
Elisabeth
E
Li
Xiang
X
Benjamin
Ivor J
IJ
Gustin
Pascal
P
D000818:Animals; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002105:Cadmium Poisoning / Q000378:metabolism / Q000503:physiopathology*; D002452:Cell Count; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D000076249:Heat Shock Transcription Factors; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008171:Lung Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D010991:Plethysmography; D014157:Transcription Factors
D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D014157:Transcription Factors; D007770:L-Lactate Dehydrogenase