Effects of neutrophil elastase inhibitor (ONO-5046) on lung injury after intestinal ischemia-reperfusion.
The underlying mechanisms of lung endothelial injury after intestinal ischemia-reperfusion (I/R) injury are not fully known. Here we investigated the effects of posttreatment with a neutrophil elastase inhibitor (NEI; ONO-5046) on lung injury after intestinal I/R injury in a rat model. Intestinal I/R was produced by 90 min of ischemia followed by either 60 or 240 min of reperfusion. For all experimental groups, the endothelial permeability index increased, neutrophil H(2)O(2) production increased in the pulmonary vasculature blood, neutrophil counts increased in bronchoalveolar lavage fluid (BALF), and the cytokine-induced neutrophil chemoattractant (CINC)-1 and CINC-3 levels were increased in BALF after 240 min (P < 0.01). In rats treated with NEI from 60 min after reperfusion, the lung endothelial permeability index was significantly reduced (P < 0.05), whereas neutrophil H(2)O(2) production in pulmonary vasculature blood and neutrophil count in BALF were significantly suppressed by NEI (P < 0.05 and P < 0.01, respectively). In addition, NEI significantly suppressed the increase of CINC-1 and CINC-3 levels in BALF (P < 0.05). Our study clearly indicates that posttreatment with NEI reduces neutrophil activation in the pulmonary vessels and neutrophil accumulation in the lungs and suggests that ONO-5046, even when administered after the primary intestinal insult, can prevent the progression of lung injury associated with intestinal I/R.
Takayama
M
M
Division of Respiratory Medicine, Department of Internal Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
Ishibashi
M
M
Ishii
H
H
Kuraki
T
T
Nishida
T
T
Yoshida
M
M
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D054360:Chemokine CXCL1; D018925:Chemokines / Q000096:biosynthesis; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000378:metabolism; D015633:Extravascular Lung Water / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006133:Growth Substances / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D007422:Intestines / Q000473:pathology*; D007958:Leukocyte Count; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008833:Microcirculation / Q000502:physiology; D020556:Neutrophil Infiltration / Q000502:physiology; D011652:Pulmonary Circulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
D054360:Chemokine CXCL1; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C513297:Cxcl1 protein, rat; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D006861:Hydrogen Peroxide; C069195:sivelestat; D019272:Leukocyte Elastase; D005998:Glycine