Sodium salicylate prevents paraquat-induced apoptosis in the rat lung.
The nonselective contact herbicide, paraquat (PQ), is a strong pneumotoxicant, especially due to its accumulation in the lung through a polyamine uptake system and to its capacity to induce redox cycling, leading to oxidative stress-related damage. In the present study, we aimed to investigate the occurrence of apoptotic events in the lungs of male Wistar rats, 24, 48, and 96 h after PQ exposure (25 mg/kg ip) as well as the putative healing effects provided by sodium salicylate [(NaSAL), 200 mg/kg ip] when administered 2 h after PQ. PQ exposure resulted in marked lung apoptosis, in a time-dependent manner, characterized by the "ladder-like" pattern of DNA observed through electrophoresis and by the presence of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL)-positive cells (TPC) as revealed by immunohistochemistry. The two main caspase cascades (the extrinsic receptor-mediated and the intrinsic mitochondria-mediated) and the expressions of p53 and activator protein-1 (AP-1) were also evaluated, to obtain an insight into apoptotic cellular signaling. PQ-exposed rats suffered a time-dependent increase of caspase-3 and caspase-8 and a decrease of caspase-1 activities in lungs compared to the control group. A marked mitochondrial dysfunction evidenced by cytochrome c (Cyt c) release was also observed as a consequence of PQ exposure. In addition, fluorescence electrophoretic mobility shift assay (fEMSA) revealed a transcriptional induction of the p53 and AP-1 transcription factors in a time-dependent manner as a consequence of PQ exposure. NaSAL treatment resulted in the remission of the observed apoptotic signaling and consequently of lung apoptosis. Taken together, the present results showed that PQ activates several events involved in the apoptotic pathways, which might contribute to its lung toxicodynamics. NaSAL, a recently implemented antidote for PQ intoxications, proved to protect lungs from PQ-induced apoptosis.
Dinis-Oliveira
R J
RJ
REQUIMTE, Departamento de Toxicologia, Faculdade de Farmácia, Universidade do Porto, Rua Aníbal Cunha, 164, 4099-030 Porto, Portugal. ricardinis@ff.up.pt
Sousa
C
C
Remião
F
F
Duarte
J A
JA
Ferreira
R
R
Sánchez Navarro
A
A
Bastos
M L
ML
Carvalho
F
F
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000032:analysis / Q000378:metabolism; D045304:Cytochromes c / Q000032:analysis / Q000378:metabolism; D004247:DNA / Q000032:analysis; D024202:Electrophoretic Mobility Shift Assay; D006540:Herbicides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D020287:In Situ Nick-End Labeling; D008168:Lung / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D008297:Male; D010269:Paraquat / Q000037:antagonists & inhibitors* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D012980:Sodium Salicylate / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000032:analysis / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000378:metabolism; D015854:Up-Regulation
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006540:Herbicides; D018808:Transcription Factor AP-1; D016159:Tumor Suppressor Protein p53; D045304:Cytochromes c; D004247:DNA; D020169:Caspases; D010269:Paraquat; D012980:Sodium Salicylate