Effects of N-acetylcysteine plus deferoxamine in lipopolysaccharide-induced acute lung injury in the rat.
OBJECTIVE
Interventions that reduce the generation or the effects of reactive oxygen species exert controversial effects in animal models of lung injury, and these could be secondary to the pro-oxidant effects of antioxidants generally by their interaction with iron. We here describe the effects of N-acetylcysteine, deferoxamine, or both in the treatment of acute lung injury induced by intratracheal lipopolysaccharide injection.


METHODS
Prospective, randomized, controlled experiment.


METHODS
Animal basic science laboratory.


METHODS
Male Wistar rats, weighing 200-250 g.


METHODS
Rats exposed intratracheally to lipopolysaccharide were treated with N-acetylcysteine (20 mg/kg subcutaneously 3, 6, and 12 hrs after lipopolysaccharide instillation), deferoxamine (20 mg/kg subcutaneously 3 hrs after lipopolysaccharide instillation), N-acetylcysteine (20 mg/kg, 3, 6, and 12 hrs after lipopolysaccharide instillation) plus deferoxamine (20 mg/kg 3 hrs after lipopolysaccharide instillation), or vehicle.


RESULTS
Acute lung injury was induced by intratracheal instillation of lipopolysaccharide in Wistar rats. The animals were randomly divided into five groups: group 1, control with instillation of isotonic saline; group 2, lipopolysaccharide treated with saline; group 3, lipopolysaccharide treated with N-acetylcysteine; group 4, lipopolysaccharide treated with deferoxamine; and group 5, lipopolysaccharide treated with N-acetylcysteine plus deferoxamine. Several times after lipopolysaccharide instillation, the rats were killed and a bronchoalveolar lavage was performed to determine thiobarbituric acid reactive species, protein carbonyls, superoxide dismutase and catalase activities, mitochondrial superoxide production (oxidative stress variables), the degree of the alveolar-capillary membrane compromise, and inflammatory infiltration. Samples from the lung were isolated and assayed for oxidative stress variables or histopathologic analyses. N-acetylcysteine plus deferoxamine decreased bronchoalveolar lavage fluid protein, inflammatory cells, oxidative damage variables, and proinflammatory cytokines. N-acetylcysteine plus deferoxamine treatment significantly attenuated lung oxidative damage, mitochondrial superoxide production, and histopathologic alterations after lipopolysaccharide instillation.


CONCLUSIONS
Our data provide the first experimental demonstration that N-acetylcysteine plus deferoxamine decreases oxidative stress and mitochondrial dysfunction and limits inflammatory response and alveolar pathology induced by lipopolysaccharide in the rat.
Ritter
Cristiane
C
Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
da Cunha
Aline Andrea
AA
Echer
Isabel Cristina
IC
Andrades
Michael
M
Reinke
Adalisa
A
Lucchiari
Newton
N
Rocha
João
J
Streck
Emílio Luiz
EL
Menna-Barreto
Sérgio
S
Moreira
José Cláudio F
JC
Dal-Pizzol
Felipe
F
D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry*; D003676:Deferoxamine / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D007375:Interleukin-1 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017262:Siderophores / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*
D007375:Interleukin-1; D008070:Lipopolysaccharides; D017262:Siderophores; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D003676:Deferoxamine; D000111:Acetylcysteine