Abstract
Early studies with first-generation poly (ADP-ribose) polymerase (PARP) inhibitors have already indicated some therapeutic potential for sulfur mustard (SM) injuries. The available novel and more potential PARP inhibitors, which are undergoing clinical trials as drugs for cancer treatment, bring it back to the centre of interest. However, the role of PARP-1 in SM-induced injury is not fully understood. In this study, we selected a high potent specific PARP inhibitor ABT-888 as an example to investigate the effect of PARP inhibitor in SM injury. The results showed that in both the mouse ear vesicant model (MEVM) and HaCaT cell model, PARP inhibitor ABT-888 can reduce cell damage induced by severe SM injury. ABT-888 significantly reduced SM induced edema and epidermal necrosis in MEVM. In the HaCaT cell model, ABT-888 can reduce SM-induced NAD+/ATP depletion and apoptosis/necrosis. Then, we studied the mechanism of PARP-1 in SM injury by knockdown of PARP-1 in HaCaT cells. Knockdown of PARP-1 protected cell viability and downregulated the apoptosis checkpoints, including p-JNK, p-p53, Caspase 9, Caspase 8, c-PARP and Caspase 3 following SM-induced injury. Furthermore, the activation of AKT can inhibit autophagy via the regulation of mTOR. Our results showed that SM exposure could significantly inhibit the activation of Akt/mTOR pathway. Knockdown of PARP-1 reversed the SM-induced suppression of the Akt/mTOR pathway. In summary, the results of our study indicated that the protective effects of downregulation of PARP-1 in SM injury may be due to the regulation of apoptosis, necrosis, energy crisis and autophagy. However, it should be noticed that PARP inhibitor ABT-888 further enhanced the phosphorylation of H2AX (S139) after SM exposure, which indicated that we should be very careful in the application of PARP inhibitors in SM injury treatment because of the enhancement of DNA damage.
Highlights
Sulfur mustard (SM), a chemical warfare vesicant agent, has been used in several military conflicts, including World Wars I and II and the Iran-Iraq War (Balali-Mood & Hefazi, 2006)
poly (ADP-ribose) polymerase-1 (PARP-1) activation increased in HaCaT cell following SM treatment, which could be prevented by ABT-888
These results suggested that the SM injury could cause poly (ADP-ribose) polymerase (PARP)-1 activation, which could be marked inhibited by the potent PARP inhibitor ABT-888
Summary
Sulfur mustard (SM), a chemical warfare vesicant agent, has been used in several military conflicts, including World Wars I and II and the Iran-Iraq War (Balali-Mood & Hefazi, 2006). Dermal exposure of SM results in severe chemical burns, affecting all layers of the skin, which produces subepidermal blisters, erythema and inflammation (Balali-Mood & Hefazi, 2005; Ghanei et al, 2010; Naraghi, Mansouri & Mortazavi, 2005). In response to DNA damage, several key biochemical pathways important in protecting cells against injury and initiating repair processes are activated. PARP-1 uses NAD+ as a substrate to catalyze covalent binding of poly (ADP-ribose) (PAR) to PARP-1 itself and some other nuclear proteins involved in DNA repair, inflammation, apoptosis/ necrosis and autophagy (Sodhi, Singh & Jaggi, 2010). PARP-1 activation had been considered to have a positive effect on cell survival by promoting DNA repair, overactivation of PARP-1 initiated by severe SM-induced DNA damage and the consequent depletion of NAD+ exacerbated the cell death instead. Little is known about the relationship between the apoptosis and autophagy pathways and the protective effect of PARP-1 inhibitors in SM-induced injury
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