Enzyme found in blood vessels likely target to treat lung injury
Lung injury due to infection, such as in sepsis, accounts for hundreds of thousands of hospitalizations a year. Sepsis occurs in 2 percent of hospital admissions and is associated with a death rate of about 50 percent. Many of these patients require ventilation to support their breathing, which may in itself produce additional injury to the lung. Yet, there are few available treatments for lung injury associated with sepsis or ventilation.
Now, scientists at Northwestern University have demonstrated that an enzyme vital to normal function of blood vessels also can be an Achilles heel during infection-induced or ventilator-induced lung injury. They believe that the enzyme holds significant potential as a drug discovery target for the treatment of acute lung injury.
As described in the May issue of Proceedings of the National Academy of Sciences, Mark Wainwright, M.D., and D. Martin Watterson identified a molecule, called myosin light chain kinase 210 (MLCK 210), that makes endothelial cells in the lung susceptible to injury during periods of inflammation.
Wainwright is assistant professor of pediatrics at the Feinberg School of Medicine at Northwestern University and a researcher at the Childrens Memorial Institute for Education and Research. Watterson is J.G. Searle Professor of Molecular Biology and Biochemistry, professor of molecular pharmacology and biological chemistry at the Feinberg School and director of the Northwestern University Drug Discovery Training Program.
Endothelial cells line blood vessels throughout the body and serve as a barrier to keep toxins in the blood from entering tissues and organs. MLCK 210 regulates normal endothelial cell function, but the contribution of MLCK 210 to the mechanisms of lung injury in the living animal was unknown.
Wainwright said that cell culture (or, in vitro) studies have identified several enzymes, including MLCK 210, in the regulation of endothelial barrier function, but no one had integrated the in vitro studies with disease injury and MLCK 210 function in a living animal.
Watterson genetically engineered mice that are missing the gene that codes for MLCK 210. The researchers exposed mice lacking MLCK 210 to a bacterial toxin that causes tissue injury as a result of severe infection. The MLCK 210 knockout mice are less susceptible to acute lung injury and also showed significant improvement in survival when exposed to a combination of toxin exposure and subsequent ventilator-induced injury.
This sequential injury is reminiscent of the clinical situation with life support for a critically ill patient.
The researchers also developed an MLCK inhibitor, an experimental drug that blocks the function of the enzyme, which they injected into normal mice with an intact MLCK 210 gene.
Normal mice exposed to bacterial toxin and ventilator-induced injury were protected by a single injection of the MLCK 210 inhibitor, a finding identical to that in the genetically altered mice lacking the MLCK 210 gene.
The researchers believe that their results and will enable scientists to conduct further studies involving the role of endothelial cells in heart disease, stroke and neurodegeneration, areas that the National Institutes of health has identified as a key research priority.
Co-authors were Janet Rossi; James Schavocky; Susan Crawford; David Steinhorn; Anastasia V. Velentza; Magdalena Zasadzki; Vladimir Shirinsky; Yuzhi Jia; Jacques Haiech; and Linda Van Eldik.
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