title: Nonmuscle myosin light chain kinase regulates murine asthmatic inflammation.
abstract: Myosin light chain kinase (MLCK; gene code, MYLK) is a multifunctional enzyme involved in isoform-specific nonmuscle (nm) and smooth muscle contraction, inflammation, and vascular permeability, processes directly relevant to asthma pathobiology. In this report, we highlight the contribution of the nm isoform (nmMLCK) to asthma susceptibility and severity, supported by studies in two lines of transgenic mice with knocking out nmMLCK or selectively overexpressing nmMLCK in endothelium. These mice were sensitized to exhibit ovalbumin-mediated allergic inflammation. Genetically engineered mice with targeted nmMLCK deletion (nmMLCK(-/-)) exhibited significant reductions in lung inflammation and airway hyperresponsiveness. Conversely, mice with overexpressed nmMLCK in endothelium (nmMLCK(ec/ec)) exhibited elevated susceptibility and severity in asthmatic inflammation. In addition, reduction of nmMLCK expression in pulmonary endothelium by small interfering RNA results in reduced asthmatic inflammation in wild-type mice. These pathophysiological assessments demonstrate the positive contribution of nmMLCK to asthmatic inflammation, and a clear correlation of the level of nmMLCK with the degree of experimental allergic inflammation. This study confirms MYLK as an asthma candidate gene, and verifies nmMLCK as a novel molecular target in asthmatic pathobiology.
authors.affiliation: 1 Arizona Respiratory Center and Department of Medicine, University of Arizona, Tucson, Arizona.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.forename: Liliana
authors.initials: L
authors.lastname: Moreno-Vinasco
authors.forename: Shwu-Fan
authors.initials: SF
authors.lastname: Ma
authors.forename: Tong
authors.initials: T
authors.lastname: Zhou
authors.forename: Yuka
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Saad
authors.initials: S
authors.lastname: Sammani
authors.forename: Yulia
authors.initials: Y
authors.lastname: Epshtein
authors.forename: D Martin
authors.initials: DM
authors.lastname: Watterson
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dudek
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
mesh_terms: D000818:Animals; D001249:Asthma / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D004727:Endothelium / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008168:Lung / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009219:Myosin-Light-Chain Kinase / Q000235:genetics / Q000378:metabolism*; D011014:Pneumonia / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D009219:Myosin-Light-Chain Kinase