Submitted to: American Journal of Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/8/2001
Publication Date: 8/1/2001
Citation: Lentsch, A.B., Kato, A., Saari, J.T., Schuscke, D.A. 2001. Augmented metalloproteinase activity and acute lung injury in copper-deficient rats. American Journal of Physiology. 281:L387-L393.
Interpretive Summary: One of the effects of dietary copper restriction that is observed in laboratory animals is impaired immune function. This impairment renders the animal less capable of responding to an injury or inflammatory insult. To further clarify the mechanism of this effect, we examined the response of copper-deficient rats to lung damage caused by an inflammatory agent. Rats were fed either a copper-adequate or a copper-deficient diet for five weeks. After instillation of the inflammatory agent into their lungs, rats fed the copper-deficient diet showed greater microscopically observable lung damage and greater leakage of protein from blood into the lung tissue, both apparent indicators of increased inflammation. However, neither an increase in a chemical mediator that is normally released in inflammation nor in white cells (immune cells) was observed in lungs of copper-deficient rats. Further analysis indicated that activities of two enzymes that are capable of damaging proteins responsible for lung structural integrity were increased in copper-deficient rats. This indicates that, for this particular model of lung injury, increased lung damage is not caused by an increase of the inflammatory response but by an independent mechanism, the increased activity of specific enzymes. This research has relevance to lung diseases such as acute respiratory distress syndrome (ARDS) and will be of interest to scientists and consumers interested in the relationship of copper nutrition to immune function.
Technical Abstract: Dietary copper is required for normal function of more than 30 mammalian enzyme systems. Copper deficiency causes a number of cardiovascular defects as well as impaired immune cell function. Little is known regarding the effects of copper deficiency on acute inflammatory responses, but this topic is relevant because most of the western population takes in far less than the recommended dietary allowance of copper. In the current studies, we investigated the effects of dietary copper deficiency on acute lung injury induced by intrapulmonary deposition of IgG immune complexes. Weanling male Long Evans rats were fed diets either adequate (5.6 ug/g) or deficient (0.3 ug/g) for copper. IgG immune complex lung injury was greatly increased in copper-deficient rats, as determined by lung vascular leak of albumin and histopathology. However, no change was observed in either the lung content of tumor necrosis factor-alpha (TNF alpha) or lung neutrophil accumulation. Lungs from copper-deficient rats had much higher levels of matrix metalloproteinase-2 (MMP-2) and MMP-9 than did copper adequate controls. This increased activity was not attributable to alveolar macrophages or neutrophils. These data suggest that the augmented lung injury caused by copper deficiency is due to increased pulmonary MMP-2 and MMP-9 activity, and not a generalized amplification of the inflammatory response.