Nonmuscle myosin light chain kinase regulates murine asthmatic inflammation.

TitleNonmuscle myosin light chain kinase regulates murine asthmatic inflammation.
Publication TypeJournal Article
Year of Publication2014
AuthorsWang T, Moreno-Vinasco L, Ma S-F, Zhou T, Shimizu Y, Sammani S, Epshtein Y, D Watterson M, Dudek SM, Garcia JGN
JournalAm J Respir Cell Mol Biol
Volume50
Issue6
Pagination1129-35
Date Published2014 Jun
ISSN Number1535-4989
KeywordsAnimals, Asthma, Cytokines, Endothelial Cells, Endothelium, Leukocytes, Lung, Mice, Mice, Knockout, Mice, Transgenic, Myosin-Light-Chain Kinase, Pneumonia
Abstract

<p>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.</p>

DOI10.1165/rcmb.2013-0434OC
Alternate JournalAm. J. Respir. Cell Mol. Biol.
PubMed ID24428690
PubMed Central IDPMC4068916
Grant ListHL 58064 / HL / NHLBI NIH HHS / United States
R56 HL088144 / HL / NHLBI NIH HHS / United States
HL 91899 / HL / NHLBI NIH HHS / United States
HL 88144 / HL / NHLBI NIH HHS / United States
R01 HL088144 / HL / NHLBI NIH HHS / United States
P01 HL058064 / HL / NHLBI NIH HHS / United States