PARP-1 Inhibitor, DPQ, Attenuates LPS-Induced Acute Lung Injury through Inhibiting NF-κB-Mediated Inflammatory Response

Abstract

Acute lung injury (ALI) is characterized by overwhelming lung inflammation and anti-inflammation treatment is proposed to be a therapeutic strategy for ALI. Poly (ADP-ribose) polymerase-1 has been demonstrated to be involved in tissue inflammation and one of its inhibitors, 3, 4-Dihydro-5[4-(1-piperindinyl)butoxy]-1(2H)-isoquinoline (DPQ), exerts anti-inflammatory effect. However, it is still unclear whether the DPQ possesses the protective effect on ALI and what mechanisms are involved. In this study, we tested the effect of DPQ on the lung inflammation induced by lipopolysaccharide (LPS) challenge in mice. We found that 6 h-LPS challenge induced significant lung inflammation and vascular leakage in mice. Treatment with DPQ at the dose of 10 μg/kg markedly reduced the neutrophil infiltration, myeloperoxidase activity and up-regulation of pro-inflammatory mediators and cytokines. LPS-elevated vascular permeability was decreased by DPQ treatment, accompanied by the inhibition of apoptotic cell death in mice lungs. In addition, we isolated mice peritoneal macrophages and showed pretreatment with DPQ at 10 μM inhibited the production of cytokines in the macrophages following LPS stimulation. DPQ treatment also inhibited the phosphorylation and degradation of IκB-α, subsequently blocked the activation of nuclear factor (NF)-κB induced by LPS in vivo and in vitro. Taken together, our results show that DPQ treatment inhibits NF-κB signaling in macrophages and protects mice against ALI induced by LPS, suggesting inhibition of Poly (ADP-ribose) polymerase-1 may be a potential and effective approach to resolve inflammation for the treatment of ALI.

Chronic Alcohol Exposure Enhances Lipopolysaccharide-Induced Lung Injury in Mice: Potential Role of Systemic Tumor Necrosis Factor-Alpha

“…Studies have shown that neutrophil migration into the lung is at least partially mediated by the chemokines MIP-2 and KC (Lomas-Neira et al 2004). Indeed, both MIP-2 and KC have been linked to acute lung injury caused by systemic LPS (Wang et al 2013; Su et al 2014) by mediating neutrophil recruitment via activation of CXCR2 (Reutershan et al 2006). The work presented here shows that LPS-induced MIP-2 and KC expression in the lung was enhanced by ethanol exposure.…”

The molecular basis of the non-thyroidal illness syndrome

“…VILI leads to local increases of TNFa, IL6 and IL1b, again suggesting the involvement of cytokines in the upregulation of Dio2 (Barca-Mayo et al 2011) via NF-kB activation (Lentsch et al 1998, Leeper-Woodford & Detmer 1999. Indeed, inhibiting NF-kB activation protects mice from LPS induced acute lung injury (Wang et al 2013). Interestingly, TH metabolism is also tightly linked with the innate immune system.…”

The clinically used PARP inhibitor olaparib improves organ function, suppresses inflammatory responses and accelerates wound healing in a murine model of third‐degree burn injury

“…(reviewed in Jagtap and Szabo, 2005) and is comparable to the effect of other, earlier-generation PARP inhibitors, as well as genetic PARP1 deficiency in various models of critical illness and systemic inflammation (Jagtap et al, 2002;Liaudet et al, 2002;Soriano et al, 2002Soriano et al, , 2006Shimoda et al, 2003;Farivar et al, 2004;Szabo, 2007;Wang et al, 2013;Liu et al, 2015;Walko et al, 2015;Zhang et al, 2015). Thus, olaparib -although originally developed and optimized for the purposes of cancer therapy -performs as expected as a PARP inhibitor in the context of inflammation, organ injury and critical illness.…”