The role of metallothionein in the pathogenesis of acute lung injury.
Often fatal, acute lung injury has a complicated etiology. Previous studies from our laboratory in mice have demonstrated that survival during acute lung injury is a complex trait governed by multiple loci. We also found that the increase in metallothionein (MT) is one of the greatest noted in transcriptome-wide analyses of gene expression. To assess the role of MT in nickel-induced acute lung injury, the survival of Mt-transgenic, Mt1/2(+/+), and Mt1/2(-/-) mice was compared. Pulmonary inflammation and global gene expression were compared in Mt1/2(+/+) and Mt1/2(-/-) mice. Gene-targeted Mt1/2(-/-) mice were more susceptible than Mt1/2(+/+) mice to nickel-induced inflammation, surfactant-associated protein B transcript loss, and lethality. Similarly, Mt-transgenic mice exhibited increased survival. MAPPFinder analyses also noted significant decreases in genes involved in protein processing (e.g., ubiquitination, folding), which were greater in Mt1/2(-/-) mice as compared with Mt1/2(+/+) mice early in the progression of acute lung injury, possibly due to a zinc-mediated transcript destabilization. In contrast, transcript levels of genes associated with the inflammatory response, extracellular matrix regulation, and coagulation/fibrinolysis were increased more in Mt1/2(-/-) mice as compared with Mt1/2(+/+) mice late in the development of acute lung injury. Thus, MT ultimately improves survival in the progression of acute lung injury in mice. Transcriptome-wide analysis suggests that this survival may be mediated through changes in the destabilization of transcripts associated with protein processing, the subsequent augmentation of transcripts controlling inflammation, extracellular matrix regulation, coagulation/fibrinolysis, and disruption of surfactant homeostasis.
Wesselkamper
Scott C
SC
Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, OH 45267-0056, USA.
McDowell
Susan A
SA
Medvedovic
Mario
M
Dalton
Timothy P
TP
Deshmukh
Hitesh S
HS
Sartor
Maureen A
MA
Case
Lisa M
LM
Henning
Lisa N
LN
Borchers
Michael T
MT
Tomlinson
Craig R
CR
Prows
Daniel R
DR
Leikauf
George D
GD
D000818:Animals; D018450:Disease Progression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009532:Nickel / Q000633:toxicity; D020411:Oligonucleotide Array Sequence Analysis; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D015996:Survival Rate
C029938:nickel sulfate; D009532:Nickel; D008668:Metallothionein