Gene expression changes during the development of acute lung injury: role of transforming growth factor beta.
BACKGROUND
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.


OBJECTIVE
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.


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.
Wesselkamper
Scott C
SC
Department of Environmental Health, P.O. Box 670056, University of Cincinnati, Cincinnati, OH 45267-0056, USA. george.leikauf@uc.edu
Case
Lisa M
LM
Henning
Lisa N
LN
Borchers
Michael T
MT
Tichelaar
Jay W
JW
Mason
John M
JM
Dragin
Nadine
N
Medvedovic
Mario
M
Sartor
Maureen A
MA
Tomlinson
Craig R
CR
Leikauf
George D
GD
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects / Q000235:genetics; D015870:Gene Expression; D051379:Mice; D009532:Nickel / Q000633:toxicity; D020411:Oligonucleotide Array Sequence Analysis; D037701:Pulmonary Surfactant-Associated Protein B / Q000235:genetics* / Q000378:metabolism; D012313:RNA / Q000235:genetics*; D012128:Respiratory Distress Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000627:therapeutic use; D053773:Transforming Growth Factor beta1
D037701:Pulmonary Surfactant-Associated Protein B; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D012313:RNA; D009532:Nickel