Inhibition of Rho kinase by fasudil hydrochloride attenuates lung injury induced by intestinal ischemia and reperfusion.
OBJECTIVE
The aim of this study is to evaluate the role of Rho-kinase in the pathogenesis of lung injury induced by intestinal ischemia/reperfusion (I/R) and the preconditioning effects of fasudil hydrochloride. The novel therapeutic approach of using Rho-kinase inhibitors in the treatment of intestinal I/R is introduced.


METHODS
Sprague-Dawley (SD) rats were divided into 4 groups: intestinal I/R group, two fasudil pretreatment groups (7.5 mg/kg and 15 mg/kg), and controls. Intestinal and lung histopathology was evaluated; myeloperoxidase (MPO) and superoxide dismutase (SOD) levels in lung parenchyma were determined. Serum tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were measured. eNOS and P-ERM expression were measured by Western Blot.


RESULTS
Lung and intestinal injury were induced by intestinal I/R, characterized by histological damage and a significant increase in BALF protein. Compared to controls, serum TNF-α, IL-6, and lung MPO activity increased significantly in the I/R group, while SOD activity decreased. A strongly positive P-ERM expression was observed, while eNOS expression was weak. After fasudil administration, injury was ameliorated. Serum TNF-α, IL-6, lung MPO and P-ERM expression decreased significantly as compared to the I/R group, while SOD activity and eNOS expression increased significantly.


CONCLUSIONS
Rho-kinase plays a key role in the pathogenesis of lung injury induced by intestinal I/R. The inhibition of the Rho-kinase pathway by fasudil hydrochloride may prevent lung injury.
Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China.
Yang
Y
Li
Ji-Hong
JH
Yao
Xiao-Wei
XW
Hu
Zhe
Z
Fan
Li
L
Huang
Hui-Rong
HR
Jing
Ke-Xin
KX
Liu
Xiao-Feng
XF
Tian
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D055371:Acute Lung Injury / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D000818:Animals; D015850:Interleukin-6 / Q000032:analysis; D007422:Intestines / Q000098:blood supply* / Q000737:chemistry / Q000201:enzymology / Q000473:pathology; D007511:Ischemia / Q000150:complications / Q000503:physiopathology*; D008168:Lung / Q000737:chemistry / Q000201:enzymology / Q000473:pathology; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D009195:Peroxidase; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase; D054460:rho-Associated Kinases; C049347:fasudil