title: Nonmuscle myosin light chain kinase activity modulates radiation-induced lung injury.
abstract: Radiotherapy as a primary treatment for thoracic malignancies induces deleterious effects, such as acute or subacute radiation-induced lung injury (RILI). Although the molecular etiology of RILI is controversial and likely multifactorial, a potentially important cellular target is the lung endothelial cytoskeleton that regulates paracellular gap formation and the influx of macromolecules and fluid to the alveolar space. Here we investigate the central role of a key endothelial cytoskeletal regulatory protein, the nonmuscle isoform of myosin light chain kinase (nmMLCK), in an established murine RILI model. Our results indicate that thoracic irradiation significantly augmented nmMLCK protein expression and enzymatic activity in murine lungs. Furthermore, genetically engineered mice harboring a deletion of the nmMLCK gene (nmMLCK(-/-) mice) exhibited protection from RILI, as assessed by attenuated vascular leakage and leukocyte infiltration. In addition, irradiated wild-type mice treated with two distinct MLCK enzymatic inhibitors, ML-7 and PIK (peptide inhibitor of kinase), also demonstrated attenuated RILI. Taken together, these data suggests a key role for nmMLCK in vascular barrier regulation in RILI and warrants further examination of RILI strategies that target nmMLCK.
authors.affiliation: Department of Medicine and Arizona Respiratory Center, University of Arizona, Tucson, Arizona, USA; These authors contributed equally as first authors.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA; These authors contributed equally as first authors.
authors.forename: Biji
authors.initials: B
authors.lastname: Mathew
authors.affiliation: Department of Medicine and Arizona Respiratory Center, University of Arizona, Tucson, Arizona, USA.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Medicine and Arizona Respiratory Center, University of Arizona, Tucson, Arizona, USA.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Shimizu
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Alicia N
authors.initials: AN
authors.lastname: Rizzo
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dudek
authors.affiliation: Department of Radiation Oncology, University of Chicago, Chicago, Illinois, USA.
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jacobson
authors.affiliation: Department of Medicine and Arizona Respiratory Center, University of Arizona, Tucson, Arizona, USA; Southern Arizona Veterans Affairs Health Care System, Tucson, Arizona, USA.
authors.forename: Louise
authors.initials: L
authors.lastname: Hecker
authors.affiliation: Department of Medicine and Arizona Respiratory Center, University of Arizona, Tucson, Arizona, USA.
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
keywords: bronchoalveolar lavage; nonmuscle myosin light chain kinase; radiation-induced lung injury