Figure - available from: Inflammopharmacology
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Histological views from Sham (leftmost column), paraquat (second and third columns), and paraquat + 3AB (rightmost column) groups. From the top to the bottom, the images represent the consecutively higher powers of magnification, which are ×40, ×100, ×200 and ×400, respectively. In the PQ Group, pulmonary parenchyma was typical and severe alveolar edema (asterisks) were also observed (2 a–d). Massive hemorrhage throughout the parenchyma and striking mesothelial reaction with florid proliferation (arrows) was also seen in the Paraquat group (3 a–d). In the paraquat + 3AB group, intra-alveolar edema and/or alveolar hemorrhage, though less intense and focal, were still present (4 a–d) (haematoxyline and eosin stain)
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Objectives
Paraquat (PQ) is a widely used herbicide. Exposure to PQ at toxic doses can result in fatal acute lung injury. Inhibition of the poly-(ADP-ribose) polymerase (PARP) enzyme alleviates inflammation and necrosis in various pathologies. Here we aimed to evaluate the effects of PARP inhibition on PQ-induced lung damage in a rat experimental m...
Citations
... 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, wheresimilarly 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 olaparibsimilar 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 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 studyolaparib 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 olaparibsimilarly 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 [32]. ...
Poly(ADP-ribose) polymerase 1 (PARP1), as a potential target for the experimental therapy of acute lung injury (ALI), was identified over 20 years ago. However, clinical translation of this concept was not possible due to the lack of clinically useful PARP inhibitors. With the clinical introduction of several novel, ultrapotent PARP inhibitors, the concept of PARP inhibitor repurposing has re-emerged. Here, we evaluated the effect of 5 clinical-stage PARP inhibitors in oxidatively stressed cultured human epithelial cells and monocytes in vitro and demonstrated that all inhibitors (1–30 µM) provide a comparable degree of cytoprotection. Subsequent in vivo studies using a murine model of ALI compared the efficacy of olaparib and rucaparib. Both inhibitors (1–10 mg/kg) provided beneficial effects against lung extravasation and pro-inflammatory mediator production—both in pre- and post-treatment paradigms. The underlying mechanisms include protection against cell dysfunction/necrosis, inhibition of NF-kB and caspase 3 activation, suppression of the NLRP3 inflammasome, and the modulation of pro-inflammatory mediators. Importantly, the efficacy of PARP inhibitors was demonstrated without any potentiation of DNA damage, at least as assessed by the TUNEL method. These results support the concept that clinically approved PARP inhibitors may be repurposable for the experimental therapy of ALI.
... Favorable effects were observed for inhibitors of various inflammatory mediators. For instance, SB431542, a selective inhibitor of the TGF-beta type 1 receptor, almost completely attenuated PQ-induced EMT-like cellular response and subsequent fibrogenesis in A549 and NHBE cells(Yamada et al. 2015;Xie et al. 2016).Tuncer et al. (2016) reported that the ...
The herbicide paraquat (PQ; 1,1’-dimethyl-4,4’-bipyridylium dichloride) is a highly toxic organic heterocyclic herbicide that has been widely used in agricultural settings. Since its commercial introduction in the early 1960s, numerous cases of fatal PQ poisonings attributed to accidental and/or intentional ingestion of PQ concentrated formulations have been reported. The clinical manifestations of the respiratory system during the acute phase of PQ poisoning mainly include acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), followed by pulmonary fibrosis in a later phase. The focus of this review is to summarize the most recent publications related to PQ-induced lung toxicity as well as the underlying molecular mechanisms for PQ-mediated pathologic processes. Growing sets of data from in vitro and in vivo models have demonstrated the involvement of the PQ in regulating lung oxidative stress, inflammatory response, epigenetics, apoptosis, autophagy, and the progression of lung fibrosis. The article also summarizes novel therapeutic avenues based on a literature review, which can be explored as potential means to combat PQ-induced lung toxicity. Finally, we also presented clinical studies on the association of PQ exposure with the incidence of lung injury and pulmonary fibrosis.
... A combination of smoke inhalation and Pseudomonas aeroginosa instillation into sheep lungs led to decreased functionality and increased tissue damage. Administration of the PARP inhibitor INO 1001 improved parameters like hemorrhage, congestion and inflammation scores and lowered oxidative stress [40]. Ischemia of isolated perfused rat lungs led to an increase of proinflammatory cytokines like TNF and IL1b, an increase in iNOS activity and subsequent elevated PAR formation with a drop in ATP levels [41]. ...
Recent studies have clearly indicated that Poly (ADP-Ribose) Polymerase (PARP) has an essential role in various physiological and pathophysiological pathways including the signaling of DNA damage, cell death pathways, cell survival and proliferation pathways, differentiation, neuronal function and inflammation. Role of PARP has been established in cardiovascular diseases like myocardial infarction, endothelial dysfunction associated hypertension, ischemia-reperfusion injury. It also plays an important role in the pathophysiology of diabetes, inflammatory disorders, and various neurodegenerative disorders. Approaches in this area lead to the identification of 18 putative PARP sequences in the human genome. PARP-1 is a most abundantly found nuclear protein which functions to sense the DNA damage. Increased oxidative stress due to any pathophysiological condition in the body, leads to over-activation of PARP1. Over-activation of PARP1 decreases the amount of NAD+/ATP in the cell and also leads to translocation of Apoptosis-Inducing Factor (AIF) to the nucleus causing cell dysfunction and ultimately cell death. Pharmacological inhibition of PARP provides a target for the prevention of various pathological conditions because it targets a relatively late event of oxidative cell injury. Therefore, investigations on the involvement of PARP and its isoforms in diseased conditions substantiate the therapeutic window of intervention quite wide.
Poly(ADP-ribose) polymerase 1 (PARP1), the major isoform of a family of ADP-ribosylating enzymes, has been implicated in the regulation of various biological processes including DNA repair, gene transcription and cell death. The concept that PARP1 becomes activated in acute lung injury (ALI), and pharmacological inhibition or genetic deletion of this enzyme can provide therapeutic benefits has emerged over 20 years ago. The current article provides an overview of the cellular mechanisms involved in the pathogenetic roles of PARP1 in ALI, and overviews the preclinical data supporting the efficacy of PARP inhibitors. In recent years, several ultrapotent PARP inhibitors have been approved for clinical use (for the therapy of various oncological diseases): these newly-approved PARP inhibitors were recently reported to show efficacy in animal models of ALI. These observations offer the possibility of therapeutic repurposing of these inhibitors for patients with ALI. The current article lays out a potential roadmap for such repurposing efforts. In addition, the article also overviews the scientific basis of potentially applying PARP inhibitors for the experimental therapy of viral ALI, such as COVID-19-associated ARDS.
