In vivo antioxidant treatment protects against bleomycin-induced lung damage in rats.
1. This study examines the activity of the antioxidant N-acetylcysteine on bleomycin-induced pulmonary fibrosis in rats with emphasis on the early inflammatory phase. 2. Rats receiving N-acetylcysteine (300 mg kg(-1) day(-1), intraperitoneal) had less augmented lung wet weight, and lower levels of proteins, lactate dehydrogenase, neutrophil and macrophage counts in bronchoalveolar lavage fluid and lung myeloperoxidase activity with a betterment of histological score at 3 days postbleomycin. 3. A diminished lung GSH/GSSG ratio and augmented lipid hydroperoxides were observed 3 days postbleomycin. These changes were attenuated by N-acetylcysteine. Alveolar macrophages from bleomycin-exposed rats released augmented amounts of superoxide anion and nitric oxide. N-Acetylcysteine did not modify superoxide anion generation but reduced the increased production of nitric oxide. 4. N-Acetylcysteine suppressed the bleomycin-induced increased activation of lung NF-kappaB (shift assay and immunohistochemistry), and decreased the augmented levels of the early inflammatory cytokines, tumour necrosis factor-alpha, interleukin-beta, interleukin-6 and macrophage inflammatory protein-2 observed in bronchoalveolar lavage fluid at 1 and 3 days postbleomycin exposure. 5. At 15 days postbleomycin, N-acetylcysteine decreased collagen deposition in bleomycin-exposed rats (hydroxyproline content: 6351+/-669 and 4626+/-288 micro g per lung in drug vehicle- and N-acetylcysteine-treated rats, respectively; P<0.05). Semiquantitative histological assessment at this stage showed less collagen deposition in N-acetylcysteine-treated rats compared to those receiving bleomycin alone. 6. These results indicate that N-acetylcysteine reduces the primary inflammatory events, thus preventing cellular damage and the subsequent development of pulmonary fibrosis in the bleomycin rat model.
Serrano-Mollar
A
A
Department of Medical Bioanalysis, Instituto de Investigaciones Biomédicas de Barcelona (IIBB-IDIBAPS), CSIC, Barcelona, Spain.
Closa
D
D
Prats
N
N
Blesa
S
S
Martinez-Losa
M
M
Cortijo
J
J
Estrela
J M
JM
Morcillo
E J
EJ
Bulbena
O
O
D000097:Acetonitriles / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D015415:Biomarkers; D001761:Bleomycin / Q000009:adverse effects* / Q000031:analogs & derivatives*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry* / Q000166:cytology; D004195:Disease Models, Animal; D006909:Hydroxyproline / Q000378:metabolism; D007150:Immunohistochemistry; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D016676:Macrophages, Alveolar / Q000737:chemistry* / Q000166:cytology / Q000187:drug effects*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D011014:Pneumonia / Q000139:chemically induced; D011658:Pulmonary Fibrosis / Q000139:chemically induced*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000737:chemistry / Q000378:metabolism; D013997:Time Factors; D014320:Triphenylmethyl Compounds / Q000494:pharmacology
C478958:(2-Chlorophenyl)(diphenyl)acetonitrile; D000097:Acetonitriles; D000975:Antioxidants; D015415:Biomarkers; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014320:Triphenylmethyl Compounds; D001761:Bleomycin; C025703:bleomycetin; D006909:Hydroxyproline; D000111:Acetylcysteine