title: LIM kinase 1 promotes endothelial barrier disruption and neutrophil infiltration in mouse lungs.
abstract: BACKGROUND
  Disruption of endothelial barrier function and neutrophil-mediated injury are two major mechanisms underlying the pathophysiology of sepsis-induced acute lung injury (ALI). Recently we reported that endotoxin induced activation of RhoA in mice lungs that led to the disruption of endothelial barrier and lung edema formation; however, the molecular mechanism of this phenomenon remained unknown.
  
  
  OBJECTIVE
  We reasoned that LIMK1, which participates in the regulation of endothelial cell contractility and is activated by RhoA/Rho kinase pathway, could mediate RhoA-dependent disruption of endothelial barrier function in mouse lungs during ALI. And if that is the case, then attenuation of endothelial cell contractility by downregulating LIMK1 may lead to the enhancement of endothelial barrier function, which could protect mice from endotoxin-induced ALI.
  
  
  RESULTS
  Here we report that LIMK1 deficiency in mice significantly reduced mortality induced by endotoxin. Data showed that lung edema formation, lung microvascular permeability, and neutrophil infiltration into the lungs were suppressed in limk1(-/-) mice.
  
  
  CONCLUSIONS
  We identified that improvement of endothelial barrier function along with impaired neutrophil chemotaxis were the underlying mechanisms that reduced severity of ALI in limk1(-/-) mice, pointing to a new therapeutic target for diseases associated with acute inflammation of the lungs.
authors.affiliation: Department of Pharmacology , University of Illinois at Chicago, 909 S Wolcott Ave, Chicago, IL 60612, USA.
authors.forename: Matvey
authors.initials: M
authors.lastname: Gorovoy
authors.forename: Jingyan
authors.initials: J
authors.lastname: Han
authors.forename: Haiyun
authors.initials: H
authors.lastname: Pan
authors.forename: Emily
authors.initials: E
authors.lastname: Welch
authors.forename: Radu
authors.initials: R
authors.lastname: Neamu
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Jia
authors.forename: Dan
authors.initials: D
authors.lastname: Predescu
authors.forename: Stephen
authors.initials: S
authors.lastname: Vogel
authors.forename: Richard D
authors.initials: RD
authors.lastname: Minshall
authors.forename: Richard D
authors.initials: RD
authors.lastname: Ye
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
authors.forename: Tatyana
authors.initials: T
authors.lastname: Voyno-Yasenetskaya
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D002633:Chemotaxis / Q000187:drug effects; D004727:Endothelium / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D054461:Lim Kinases / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000201:enzymology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000201:enzymology* / Q000473:pathology; D011654:Pulmonary Edema / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D018805:Sepsis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: D008070:Lipopolysaccharides; C440499:lipopolysaccharide, Escherichia coli O111 B4; D054461:Lim Kinases; C515893:Limk1 protein, mouse; D054460:rho-Associated Kinases; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
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