Unexpected Drug Works for Lung Injury August 2005 Scientists from Johns Hopkins University have discovered that the cholesterol-lowering drug, simvastatin, can be used to treat acute lung injury, a fatal condition with no effective treatment. By studying the disease at the molecular level, they found over 400 genes involved in disease progression, providing critical new targets for treatments that could prevent acute lung injury. Acute lung injury (ALI) is the sudden onset of inflammation and vascular permeability in the lung which can occur following surgery, bacterial infection or blood transfusion. ALI has a 40 percent fatality rate, killing an estimated 35 to 40 thousand people per year. The disease has been nearly impossible to treat because scientists haven't been able to figure out how ALI progresses at the molecular level. In the June 2005 issue of AJP - Lung Cellular and Molecular Physiology, Dr. Joe Garcia's group reports that mice treated with simvastatin were protected from ALI induced by bacterial toxins. The group found that simvastatin treatment reduced vascular leakage and inflammation — causes of respiratory failure — by over 50 percent. Garcia and colleagues used Affymetrix GeneChip® microarrays to explain how a drug used to treat high cholesterol could work for ALI. Using the arrays, the team identified two critical genes, IL6 and CCL22, that were highly expressed in mice treated with bacterial toxins, but reduced in mice treated with the toxins plus simvastatin. IL6 activates inflammatory cells and has been previously shown to be elevated in ALI, while CCL22 attracts other inflammatory cells. Their discovery offers one of the first explanations of how a drug like simvastatin may help block ALI. Using the GeneChip® Mouse Genome 430 2.0 Array, the group was able to simultaneously analyze changes in nearly 35,000 genes, looking beyond the "usual-suspect" ALI genes that scientists had been studying for years. Using this whole-genome approach, the team discovered over 400 other genes that had never before been associated with ALI. These genes are known to be involved in inflammation, immune response, and cell motility, providing even more insight into the molecular pathways that cause ALI. By identifying the genetic pathways that are affected by simvastatin, Garcia's research may have found the Achilles' of acute lung injury; new drugs can be designed to counteract those pathways, providing important new weapons in the fight against ALI. The author, John Carter, received his BA in Molecular Biology from Princeton University. He is currently pursuing his MD/PhD at Northwestern University.