Effectiveness of liposomal-N-acetylcysteine against LPS-induced lung injuries in rodents.
Acute lung injury (ALI) and its most severe form, the acute respiratory distress syndrome (ARDS) are frequent complications in critically ill patients and are responsible for significant morbidity and mortality. So far, experimental evidence supports the role of oxidants and oxidative injury in the pathogenesis of ALI/ARDS. In this study, the antioxidant effects of conventional N-acetylcysteine (NAC) and liposomally entrapped N-acetylcysteine (L-NAC) were evaluated in experimental animals challenged with lipopolysaccharide (LPS). Rats were pretreated with empty liposomes, NAC, or L-NAC (25mg/kg body weight, iv); 4h later were challenged with LPS (E. coli, LPS 0111:B4) and sacrificed 20h later. Challenge of saline (SAL)-pretreated animals with LPS resulted in lung injury as evidenced by increases in wet lung weight (edema), increases in lipid peroxidation (marker of oxidative stress), decreases of lung angiotensin-converting enzyme (ACE) (injury marker for pulmonary endothelial cells) and increases in the pro-inflammatory eicosanoids, thromboxane B(2) and leukotriene B(4). The LPS challenge also increased pulmonary myeloperoxidase activity and chloramine concentrations indicative of neutrophil infiltration and activation of the inflammatory response. Pretreatment of animals with L-NAC resulted in significant increases in the levels of non-protein thiols and NAC levels in lung homogenates (p<0.05) and bronchoalveolar lavage fluids (p<0.001), respectively. L-NAC was significantly (p<0.05) more effective than NAC or empty liposomes in attenuating the LPS-induced lung injuries as indicated by the aforementioned injury markers. Our results suggested that the delivery of NAC as a liposomal formulation improved its prophylactic effectiveness against LPS-induced lung injuries.
Mitsopoulos
Panagiotis
P
Medical Sciences Division, Northern Ontario School of Medicine, Lakehead University, Ontario, Canada.
Omri
Abdelwahab
A
Alipour
Misagh
M
Vermeulen
Natasha
N
Smith
Milton G
MG
Suntres
Zacharias E
ZE
D000111:Acetylcysteine / Q000008:administration & dosage* / Q000737:chemistry; D055371:Acute Lung Injury / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage* / Q000737:chemistry; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D002700:Chloramines / Q000378:metabolism; D004195:Disease Models, Animal; D004339:Drug Compounding; D007275:Injections, Intravenous; D007975:Leukotriene B4 / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008070:Lipopolysaccharides; D008081:Liposomes; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013929:Thromboxane B2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000975:Antioxidants; D002700:Chloramines; D008070:Lipopolysaccharides; D008081:Liposomes; D013438:Sulfhydryl Compounds; D014409:Tumor Necrosis Factor-alpha; C440499:lipopolysaccharide, Escherichia coli O111 B4; D007975:Leukotriene B4; D013929:Thromboxane B2; D009195:Peroxidase; D007703:Peptidyl-Dipeptidase A; C030816:chloramine; D000111:Acetylcysteine