Suppression of plasminogen activator inhibitor-1 by inhaled nitric oxide attenuates the adverse effects of hyperoxia in a rat model of acute lung injury.
BACKGROUND
Locally increased expression of plasminogen activator inhibitor-1 (PAI-1) in acute lung injury (ALI) is largely responsible for fibrin deposition in the alveolae and lung microvasculature. In vitro, nitric oxide (NO) effectively suppresses the ischemic induction of PAI-1. We aimed to investigate the effects of inhaled NO on PAI-1 expression in ALI in a rat model with and without hyperoxia.


METHODS
Healthy adult rats were primed with lipopolysaccharide (LPS) via an intraperitoneal challenge followed by a second dose of LPS given intratracheally to induce ALI (LPS group), whereas the control groups were given sterile saline. All groups were allocated to subgroups according to gas exposure: NO (20 parts per million, NO), 95% oxygen (O), both (ONO), or room air (A). At 4h, 24h, 48h (after 4h or 24h exposure to the various gases, 24h gas intervention and then observation until 48h), the rat lungs were processed and PAI-1 protein and mRNA expression, histopathological lung injury scores and fibrin deposition were evaluated.


RESULTS
At 4 and 24h, inhaled NO caused the PAI-1 mRNA levels in the LPS-NO and LPS-ONO subgroups to decrease compared with the untreated LPS subgroups. At 48h, higher PAI-1 mRNA levels than those of the corresponding control subgroup were only observed in the LPS-O subgroup, and these values were lower in the LPS-ONO subgroup than in the LPS-O subgroup. The trends of the PAI-1 protein levels mirrored those of PAI-1 mRNA. At 48h, PAI-1 protein levels in the LPS-NO and LPS-ONO subgroups were decreased compared with those in the untreated LPS subgroups. The histopathological lung injury scores and fibrin deposition in LPS subgroups that inhaled NO showed a decreasing trend compared with the untreated LPS subgroups.


CONCLUSIONS
Inhaled NO can suppress elevated PAI-1 expression in rats with ALI induced by endotoxin. Although exposure to high-concentration oxygen prolongs the duration of PAI-1 mRNA overexpression in ALI, inhaled NO can reduce this effect and alleviate both fibrin deposition and lung injury.
Department of Pediatric Emergency Medicine and Critical Care Medicine, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102, P.R. China.
Yang
Y
Chen
Department of Pediatric Emergency Medicine and Critical Care Medicine, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102, P.R. China. Electronic address: luzhujin@hotmail.com.
Zhu-Jin
ZJ
Lu
Pediatric Institute, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102, P.R. China.
Yi
Y
Yang
Department of Pediatric Emergency Medicine and Critical Care Medicine, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102, P.R. China.
Guo-Ping
GP
Lu
Department of Pediatric Emergency Medicine and Critical Care Medicine, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102, P.R. China.
Wei-Ming
WM
Chen
Department of Pediatric Emergency Medicine and Critical Care Medicine, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102, P.R. China.
Ling-En
LE
Zhang
D055371:Acute Lung Injury / Q000150:complications* / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D000818:Animals; D001993:Bronchodilator Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D005337:Fibrin / Q000276:immunology; D018496:Hyperoxia / Q000150:complications*; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009569:Nitric Oxide / Q000627:therapeutic use*; D010100:Oxygen / Q000627:therapeutic use*; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects
D001993:Bronchodilator Agents; D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D009569:Nitric Oxide; D005337:Fibrin; D010100:Oxygen
acute lung injury; fibrin; hyperoxia; nitric oxide; plasminogen activator inhibitor-1