Paraquat Poisoning Induces TNF-α-Dependent iNOS/NO Mediated Hyporesponsiveness of the Aorta to Vasoconstrictors in Rats

Abstract

Paraquat is a toxic herbicide that may induce acute lung injury, circulatory failure and death. The present work aimed at investigating whether there is systemic inflammation and vascular dysfunction after paraquat exposure and whether these parameters were related. There was neutrophilia and accumulation of neutrophils in lung and bronchoalveolar lavage of animals given paraquat. This was associated with an increase in serum levels of TNF-α. In rats given paraquat, the relaxant response of aortic rings to acetylcholine was not modified but the contractile response to phenylephrine was greatly reduced. Endothelium removal or treatment with non-selective (L-NAME) or selective (L-NIL) inhibitors of inducible nitric oxide synthase (iNOS) restored contraction of aortas. There was greater production of nitric oxide (NO), which was restored to basal level by L-NIL, and greater expression of iNOS in endothelial cells, as seen by Western blot analyses and confocal microscopy. Blockade of TNF-α reduced pulmonary and systemic inflammation and vascular dysfunction. Together, our results clearly show that paraquat causes pulmonary and systemic inflammation, and vascular dysfunction in rats. Vascular dysfunction is TNF-α dependent, associated with enhanced expression of iNOS in aortic endothelial cells and greater NO production, which accounts for the decreased responsiveness of aortas to vasoconstrictors. Blockers of TNF-α may be useful in patients with paraquat poisoning.

The pro‐inflammatory cytokineTNF‐α inhibits lymphatic pumping via activation of theNF‐κB‐iNOSsignaling pathway

“…By showing restoration of lymphatic contraction frequency in TNF-α-treated vessels upon selective inhibition of iNOS with 1400W, our findings provide a convincing indication of the pre-eminent role of iNOS in the TNF-α-induced decrease in pumping. These data are also consistent with studies demonstrating iNOS-dependent impairment of arterial contractility by TNF-α [2,27]. Involvement of iNOS was further strengthened by qPCR data showing that the significant up-regulation of iNOS mRNA expression in lymphatic vessels treated with TNF-α was reversed in the presence of PDTC.…”

Pharmacological Inhibition of CXCR2 Chemokine Receptors Modulates Paraquat-Induced Intoxication in Rats

“…Furthermore, the acute exposure to paraquat (20 mg/kg, i.p.) produced a marked increase of neutrophil influx to the broncoalveolar lavage of mice, and this parameter was reduced by TNF-α inhibition [59]. In the present study, the repeated i.p.…”

Atorvastatin protected from paraquat-induced cytotoxicity in alveolar macrophages via down-regulation of TLR-4

“…Several pathways were clarified as pathways of oxidative injuries by PQ including: reduction of PQ by NADPH-cytochrome P450 reeducates and a subsequent redox cycle, inhibition of mitochondrial electron transport chain, and interaction with nitric oxide syntheses, NADPH oxidase and xanthine oxidase (Ranjbar et al, 2002). Another report showed that PQ enhanced expression of iNOS in aortic endothelial cells and consequently increased the NO production leading to the decreased responsiveness of aortas to vasoconstrictors (Aires et al, 2013).…”