Published ahead of print on September 15, 2005, doi:10.1165/rcmb.2005-0093OC Am. J. Respir. Cell Mol. Biol., Volume 34, Number 1, January 2006, 15-27 A more recent version of this article appeared on January 1, 2006
Submitted on March 3, 2005 Gene Expression Profiles of Mst1r Deficient Mice During Nickel-Induced Acute Lung InjuryAli Mallakin1,1 Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA, 2 Department of Environmental Health and Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA, 3 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA * To whom correspondence should be addressed. E-mail: susan.waltz{at}uc.edu.
Previous studies have shown that mice deficient in the tyrosine kinase domain (TK-/-) of the receptor Mst1r have an increased susceptibility to nickel-induced acute lung injury. Mst1r TK-/- mice have decreased survival times, alterations in cytokine and nitric oxide regulation, and an earlier onset of pulmonary pathology compared to control mice, suggesting that Mst1r signaling, in part, may regulate the response to acute lung injury. To examine the role of Mst1r in acute lung injury in more detail, we compared the gene-expression profiles of murine lung mRNA from control and Mst1r TK-/- mice at baseline and after 24-hour of particulate nickel sulfate exposure. Microarray analyses showed a total of 343 transcripts that were significantly changed, either by Ni treatment, or between genotypes. Genes responsible for inflammation, edema and lymphocyte function were altered in the Mst1r TK-/- mice. Interestingly, the genes for several granzymes were increased in Mst1r TK-/- mice prior to Ni exposure, compared to controls. In addition, the Mst1r TK-/- lungs showed clusters of cells near the vascular endothelium and airways. Immunohistochemistry indicates these clusters are composed of macrophages, T-cells and neutrophils, and that the clusters display granzyme protein production. These results suggest that Mst1r signaling may be involved in the regulation of macrophage and T-lymphocyte activation in vivo during injury. This assessment of gene expression indicates the importance of genetic factors in contributing to lung injury and points to strategies for intervention in the progression of inflammatory diseases.
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