Liposomal antioxidants provide prolonged protection against acute respiratory distress syndrome.
BACKGROUND
We have previously shown that N-acetylcysteine (NAC), an antioxidant, in the resuscitation fluid after shock prevents lung injury in response to lipopolysaccharide (LPS) by inhibiting chemokine generation by alveolar macrophages in the lung. However, the protection was short-lived. We hypothesized that liposomal (Lip) NAC delivered intratracheally might be delivered directly to the target cells and exert prolonged effect.


METHODS
Sprague-Dawley rats were bled to a blood pressure of 40 mm Hg for 1 hour and resuscitated with shed blood and equal volume of Ringer's lactate. In some studies 500 mg/kg NAC was included in the resuscitation fluid. Thirty minutes later, 150 microl LipNAC (9.4 mg/kg NAC) was given intratracheally. One hour and 18 hours after resuscitation, LPS (30 microg/kg) or saline was given intratracheally. Lung injury was assessed by permeability to (125)I-albumin, bronchoalveolar lavage neutrophils and lung myeloperoxidase. The cytokine-induced neutrophil chemoattractant (CINC) expression in the lung was assessed by Northern blot.


RESULTS
At the early time point, both NAC and LipNAC protected the lung with the effects in significantly reducing the increases in transpulmonary albumin flux, neutrophil influx and myeloperoxidase in the lungs of shock/LPS rats. However, by the late time point, only LipNAC retained its salutary effect. This correlated well with persistent ability to prevent CINC increase. In addition, Lipalpha-tocopherol (alpha-T) and LipNAC/alpha-T were tested and determined to be effective to protect the lung.


CONCLUSIONS
Liposomal encapsulation of antioxidants at low dose provides long lasting protection against acute respiratory distress syndrome after shock. This may represent a novel treatment approach.
Department of Surgery, Toronto General Hospital and University of Toronto, Ontario, Canada.
J
J
Fan
P N
PN
Shek
Z E
ZE
Suntres
Y H
YH
Li
G D
GD
Oreopoulos
O D
OD
Rotstein
D000111:Acetylcysteine / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology*; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000235:genetics; D004337:Drug Carriers; D005786:Gene Expression Regulation / Q000187:drug effects; D006133:Growth Substances / Q000235:genetics; D006470:Hemorrhage / Q000503:physiopathology; D007275:Injections, Intravenous; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000633:toxicity; D008081:Liposomes; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D009195:Peroxidase / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control*; D012151:Resuscitation
D000975:Antioxidants; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D004337:Drug Carriers; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D008081:Liposomes; D009195:Peroxidase; D000111:Acetylcysteine