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Gene expression changes during the development of acute lung injury: role of transforming growth factor beta
Scott C Wesselkamper1, Lisa M Case, Lisa N Henning
1Department of Environmental Health, P.O. Box 670056, University of Cincinnati, Cincinnati, OH 45267-0056, USA. george.leikauf@uc.edu
Rationale:
Acute lung injury can occur from multiple causes, resulting in high mortality. The pathophysiology of nickel-induced acute lung injury in mice is remarkably complex, and the molecular mechanisms are uncertain.
Objectives:
To integrate molecular pathways and investigate the role of transforming growth factor beta (TGF-beta) in acute lung injury in mice.
Methods:
cDNA microarray analyses were used to identify lung gene expression changes after nickel exposure. MAPPFinder analysis of the microarray data was used to determine significantly altered molecular pathways. TGF-beta1 protein in bronchoalveolar lavage fluid, as well as the effect of inhibition of TGF-beta, was assessed in nickel-exposed mice. The effect of TGF-beta on surfactant-associated protein B (Sftpb) promoter activity was measured in mouse lung epithelial cells.
Measurements And Main Results:
Genes that decreased the most after nickel exposure play important roles in lung fluid absorption or surfactant and phospholipid synthesis, and genes that increased the most were involved in TGF-beta signaling. MAPPFinder analysis further established TGF-beta signaling to be significantly altered. TGF-beta-inducible genes involved in the regulation of extracellular matrix function and fibrinolysis were significantly increased after nickel exposure, and TGF-beta1 protein was also increased in the lavage fluid. Pharmacologic inhibition of TGF-beta attenuated nickel-induced protein in bronchoalveolar lavage. In addition, treatment with TGF-beta1 dose-dependently repressed Sftpb promoter activity in vitro, and a novel TGF-beta-responsive region in the Sftpb promoter was identified.
Conclusions:
These data suggest that TGF-beta acts as a central mediator of acute lung injury through the alteration of several different molecular pathways.
Insights
Nickel exposure causes acute lung injury by altering molecular pathways. Transforming growth factor beta (TGF-beta) plays a key role in this complex process, impacting lung function and fluid balance.
Area of Science:
- Pulmonary Medicine
- Molecular Biology
- Toxicology
Background:
- Acute lung injury (ALI) is a severe condition with high mortality.
- The molecular mechanisms underlying nickel-induced ALI in mice are not fully understood.
- Investigating specific molecular pathways is crucial for understanding ALI pathogenesis.
Purpose of the Study:
- To elucidate the molecular pathways involved in nickel-induced ALI.
- To investigate the specific role of transforming growth factor beta (TGF-beta) in nickel-induced ALI.
- To identify potential therapeutic targets for ALI.
Main Methods:
- Gene expression profiling using cDNA microarrays to identify changes post-nickel exposure.
- Pathway analysis (MAPPFinder) to determine significantly altered molecular pathways.
- Assessment of TGF-beta1 protein levels and the effects of TGF-beta inhibition in vivo and in vitro.
Main Results:
- Nickel exposure significantly altered genes involved in lung fluid absorption and surfactant synthesis.
- TGF-beta signaling pathways were identified as significantly impacted by nickel exposure.
- TGF-beta inhibition attenuated nickel-induced lung injury, and TGF-beta repressed surfactant protein B (Sftpb) promoter activity.
Conclusions:
- TGF-beta acts as a central mediator in nickel-induced acute lung injury.
- Alterations in multiple molecular pathways driven by TGF-beta contribute to ALI.
- Targeting TGF-beta signaling may offer a therapeutic strategy for ALI.
