LIM kinase 1 promotes endothelial barrier disruption and neutrophil infiltration in mouse lungs.
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.
Gorovoy
Matvey
M
Department of Pharmacology , University of Illinois at Chicago, 909 S Wolcott Ave, Chicago, IL 60612, USA.
Han
Jingyan
J
Pan
Haiyun
H
Welch
Emily
E
Neamu
Radu
R
Jia
Zhengping
Z
Predescu
Dan
D
Vogel
Stephen
S
Minshall
Richard D
RD
Ye
Richard D
RD
Malik
Asrar B
AB
Voyno-Yasenetskaya
Tatyana
T
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
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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