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  • The redox sensitive transcription factor

    2021-07-30

    The redox sensitive transcription factor NF-κB is reported to play a crucial role in the COPD pathogenesis via up regulating the expression of several cytokines, chemokines, growth factors, and adhesion molecules [71]. Incidentally, we and others have shown that PARP-1 modulates the NF-κB activation for efficient expression of several pro-inflammatory factors [18], [21], [72]. Analysis of NF-κB activation in present model showed that olaparib blocks the NF-κB activation through suppression of phosphorylation of P65NF-κB at ser 532 without altering the phosphorylation of IκBα. Furthermore, PARP-1 inhibition reduced the mRNA expression of NF-κB dependent pro inflammatory cytokines (TNF-Α, IL-6), chemokine (MIP-2; mouse analogue of IL-8) and growth factor (GCSF). The reduction in the mRNA expression of such genes was corroborated by their reduced production at the protein level in BALF. These cytokines play a crucial role in establishment of COPD associated inflammation. In fact, the elevated levels of TNF-Α, IL-6, and/or IL-8 in serum or BALF are considered as a hallmark of the disease [45], [46]. Different studies have shown that TNF-Α depletes cellular GSH content in pulmonary tissues [73], [74]. Additionally, it is reported that TNF-Α stimulates ROS production in human endothelial m6A and neutrophils [75], [76]. The expression of adhesion molecules, which is required for infiltration of inflammatory cells in the lungs, is known to be influenced by TNF-Α [77], [78], [79]. IL-8 is the primary chemokine that is associated with chemotactic response of neutrophils. GCSF is an important growth factor that is associated with survival and proliferation of neutrophils [47]. Additionally, we observed that PARP-1 inhibition was associated with reduced expression of cell adhesion molecules ICAM-1 and VCAM-1. Overall, it appears that anti-inflammatory effects exhibited by PARP-1 inhibition were associated with reduced NF-κB activation and consequent decline in cytokines, chemokines and adhesion molecules. It is noteworthy, that the attenuation of inflammation by dexamethasone was associated with significant reduction in levels of TNF-Α, IL-6, and MCP-1 but not of KC and GCSF. Since TNF-Α has multifaceted role in driving the disease progression especially by influencing the expression of adhesion molecules [77], [78], [79], we speculate that the concomitant reduction in TNF-Α and adhesion molecules may be responsible for the pronounced reduction in inflammatory cells’ influx. However, further studies are required to negate the role of KC and GCSF in dexamethasone mediated suppression of lung inflammation in response to elastase treatment. Histone acetyltransferases (HATs) and Histone deacetylases (HDACs) regulate the inflammatory response by influencing the expression of various inflammatory genes [80]. It is now known that corticosteroids exert their anti-inflammatory effects by carrying out deacetylation of glucocorticoid receptors and consequent NF-κB inactivation [81]. In patients with COPD, reduced activity of HDACs, specifically HDAC2, has been found and is linked with steroids’ resistance in the disease [82], [83], [84]. Additionally, there are increasing number of evidences that nitrosative stress causes nitration of different tyrosine residues in HDAC2 and ultimately enzyme inactivation [85], [86]. Furthermore, Malhotra et al. reported that denitrosylation of HDAC2 by activation of the transcription factor nuclear factor erythroid 2–related factor 2 (NRF2), restored the dexamethasone sensitivity in macrophages from patients with COPD [87]. In light of earlier reports that the expression of inos, the primary enzyme associated with NO synthesis is dependent on PARP-1 activity [21], [88], [89]; we speculate that inhibition of PARP-1 may be associated with restoration of steroid sensitivity in COPD. However, future studies are required to examine this aspect.