Metallothionein is a Protective Factor in Nickel-Induced Acute Lung Injury

Scott C. Wesselkamper, Ph.D., Timothy P. Dalton, Ph.D., Michael T. Borchers, Ph.D., Daniel Prows, Ph.D. and George Leikauf, Ph.D.
University of Cincinnati
T32ES07250, R01ES10562, R01ES12463, and P30ES06096

Background: Acute lung injury, also known as acute respiratory distress syndrome, is a distinct form of respiratory disease characterized by insufficient levels of oxygen in the blood, breathing difficulties, and rapid breathing. It may develop in conjunction with widespread infection or as a result of pneumonia, trauma, shock, multiple blood transfusions, and inhalation of toxic substances. It usually develops within 24-48 hours of the original injury or illness and affects from 3 to 75/100,000 people in the general population each year. The mortality rate from acute lung injury is 20-40% and patients that do survive are often left with scarring of the lungs and reduced lung function.

Inhaled nickel has been shown to cause acute lung injury in a mouse model. It was noted in these studies that genes for the protein metallothionein were induced after the exposure. Metallothionein has been widely studied for its role in metal homeostasis and detoxification. Two of the four mouse genes for metallothionein, MT1 and MT2, are expressed in nearly all organs. In previous studies metallothionein was shown to be protective against lipopolysaccharide-induced acute lung injury.

Advance: In a new study, NIEHS­supported investigators at the University of Cincinnati Medical Center have investigated the protective role of metallothionein in ­ acute lung injury in mice. Mice without either MT1 or MT2 were more susceptible than mice homozygous for MT1 and MT2 to nickel­induced lung inflammation, disruption of surfactant production, and lethality. Microarray analysis was used to determine that genes involved in the inflammatory response, extracellular matrix regulation, and coagulation were increased more in the mice missing the metallothionein genes.

Implications: This study shows that metallothionein improves survival in the progression of acute lung injury. This survival is mediated through several processes including inflammation, surfactant production, and protein processing. The results of this study should stimulate further research into the protective role and possible clinical use of metallothionein in the treatment of acute lung injury.

Citation: Wesselkamper SC, McDowell SA, Medvedovic M, Dalton TP, Deshmukh HS, Sartor MA, Case LM, Henning LN, Borchers MT, Tomlinson CR, Prows DR, Leikauf GD. The role of metallothionein in the pathogenesis of acute lung injury. Am J Respir Cell Mol Biol. 2006 Jan;34(1):73-82. Epub 2005 Sep 15.