Pharmacological inhibition of poly (ADP-ribose) polymerase by olaparib ameliorates influenza-virus-induced pneumonia in mice

Abstract

Treatments against influenza A viruses (IAV) have to be updated regularly due to antigenic drift and drug resistance. Poly (ADPribose) polymerases (PARPs) are considered effective therapeutic targets of acute lung inflammatory injury. This study aimed to explore the effects of PARP-1 inhibitor olaparib on IAV-induced lung injury and the underlying mechanisms. Male wild-type C57BL/6 mice were intranasally infected with IAV strain H1N1 to mimic pneumonia experimentally. Olaparib at different doses was intraperitoneally injected 2 days before and 5 consecutive days after virus stimulation. On day 6 post-infection, lung tissues as well as bronchoalveolar lavage fluid (BALF) were sampled for histological and biochemical analyses. Olaparib increased the survival rate of IAV mice dose-dependently. Olaparib remarkably reduced IAV mRNA expression, myeloperoxidase (MPO) level, and inflammatory cell infiltration in IAV lungs. Moreover, olaparib significantly reduced the level of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-6, and IL-4 and increased IL-10 in IAV lungs. Also, olaparib efficiently reduced IL-6, monocyte chemotactic protein (MCP)-1, granulocyte colony-stimulating factor (G-CSF), TNF-α, chemokine (C-X-C motif) ligand (CXCL)1, CXCL10, chemokine (C-C motif) ligand (CCL)3, and regulated on activation, normal T cell expressed and secreted (RANTES) release in IAV BALF. Olaparib decreased PARylated protein content and p65, IκBα phosphorylation in IAV lung tissues. This study successfully constructed the pneumonia murine model using IAV. Olaparib decreased IAV-induced mortality in mice, lung injury, and cytokine production possibly via modulation of PARP-1/NF-κB axis.

Efficacy of Clinically Used PARP Inhibitors in a Murine Model of Acute Lung Injury

“…The principal conclusion of the current study is that clinically approved PARP inhibitors, such as olaparib and rucaparib, exert protective effects in various cell types against oxidative stress in vitro and protect the lung in an experimental model of LPS-induced lung injury. These data confirm and extend prior studies demonstrating the protective effect of various earlier-generation PARP inhibitors, or PARP1 deficiency [ 10 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ], or clinically approved PARP inhibitors such as olaparib [ 28 , 29 , 30 , 31 , 32 ] in various models of lung injury (reviewed in [ 10 ]). Although many prior studies have utilized various PARP inhibitors in various models of lung injury (and have already demonstrated that such agents protect against extravasation, pro-inflammatory pathway activation, infiltration of various immune cells [ 10 ]), specifically the available information regarding clinically approved PARP inhibitors in ALI (or, more generally, in models of lung injury) is rather limited and consists of three studies: (a) a rat model of LPS-induced lung injury, where—similarly to the current study—olaparib was found to decrease the activation/production of several pro-inflammatory signalling pathways/genes including NF-κB and TNF-α [ 28 ]; (b) a mouse model of ovalbumin-induced chronic asthma, where olaparib—similar to the current study—reduced the pulmonary infiltration of various immune cells and suppressed the activation of the NF-κB pathway and of the activation of the NLRP3 system [ 29 ] (c) a mouse model of sepsis induced by cecal ligation and puncture, where olaparib—similar to the current study—improved lung histology and exerted systemic beneficial effects without exacerbating DNA injury, as assessed by the TUNEL assay [ 30 ]; (d) a mouse model of ALI induced by intratracheal LPS administration, where—similarly to the current study—olaparib was found to decrease the activation/production of several pro-inflammatory signalling pathways/genes including NF-κB and TNF-α (and in addition, PARP inhibition also suppressed various oxidative stress markers and improved central nervous system function) [ 31 ] and (e) a model of influenza virus-induced pneumonia, where olaparib—similarly to the current study—olaparib was found to decrease the activation/production of several pro-inflammatory signalling pathways/genes including NF-κB and TNF-α […”

“…The underlying mechanisms are likely multiple: they may involve direct cytoprotective effects, regulation of various inflammatory mediators, and—as a consequence of these—suppression of inflammatory cell infiltration and attenuation of various self-amplifying cycles of cell and tissue injury. These mechanisms have already been characterized extensively in various in vitro and in vivo models using various classes of PARP inhibitors, including clinically approved ones such as olaparib [ 1 , 2 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ].…”

Sirtuin3 Alleviated Influenza A Virus-Induced Mitochondrial Oxidative Stress and Inflammation in Lung Epithelial Cells via Regulating Poly (ADP-Ribose) Polymerase 1 Activity

“…Furthermore, PARP-1 interacting with viral hemagglutinin and evoking the viral HA-induced degradation of host type I IFN receptor promoted IAV replication [43]. Another study indicated that PARP-1 inhibitor effectively decreased the secretion of pro-inflammatory mediators and inflammatory cell infiltration by enhancing PARP-1 activity with PARylation accumulation and resulted in inhibition of IAV-induced lung injury [44]. In this study, we also observed that PARP-1 expression had no change in cells after IAV infection and overexpression of Sirt3.…”

“…Previous studies have shown that the inhibition of PARP-1 activity alleviated IAV-infected pneumonia [24]. We next explored the role of PARP-1 in Sirt3-mediated IAV injury in lung epithelial cells.…”

ADP‐ribosylation in evasion, promotion and exacerbation of immune responses

“…Indeed, in acute lung injury animal models, PARP inhibitors reduced inflammatory mediators and activation of NFAT and NF‐κB in macrophages, improved the Th17‐to‐Foxp3 T‐cell ratio and decreased inflammation [124,125]. In a mouse model of influenza virus A‐associated pneumonia, the PARP inhibitor olaparib drastically reduced lung cell infiltration, chemokine production and inflammatory cytokines, increasing survival [126]. Moreover, the picture may be even more complex because during acute lung inflammation, there are systemic effects leading to CNS inflammation and cognitive impairments, as described in survived patients [127].…”