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  • Apart from neutrophil mediated inflammation the production o


    Apart from neutrophil-mediated inflammation, the production of pro-inflammatory cytokines and chemokines from PGD2/CRTH2 activated macrophages could further aggravate LPS-induced lung injury (Eguchi et al., 2011; Jandl et al., 2016). Interestingly, genetic ablation of CRTH2 diminishes the TNF-α production in sepsis, a common cause of ALI (Ishii et al., 2012). However, the macrophage-derived IL-1β and TNF-α, as early response cytokines following LPS-induced lung injury, elicit an inflammatory cascade through direct damage to the vascular endothelial and alveolar epithelial cells. This results in the secretion of another pro-inflammatory cytokine, such as IL-6 (Mukhopadhyay et al., 2006) and neutrophil chemokines, such as IL-8 (Kim et al., 2010), thereby further intensifying the inflammation process. Notably, pro-inflammatory cytokines including IL-1β, TNF-α, and IL-6 (Strieter and Kunkel, 1994) and a chemokine IL-8 (Hammond et al., 1995; Singer and Sansonetti, 2004) trigger an intense migration of neutrophils across the endothelial barrier. Elevated levels of pro-inflammatory cytokines and chemokines have been identified in BAL fluid of patients with ALI/ARDS (Goodman et al., 1996), while attenuation of pro-inflammatory cytokines and chemokines levels in LPS-induced animal models leads to the reduced lung injury (Li et al., 2016). Similarly, in our study, LPS exposure increases the Lonafarnib of IL-1β, TNF-α, IL-6 and KC (the mouse homologue of IL-8) in the BAL fluid of the murine ALI model mice, when compared with control mice. However, CT-133 treatment markedly suppresses this overexpression by blocking CRTH2. Likewise, Lonafarnib the ELISA and RT-PCR results reveal that LPS and PGD2 treatments of RAW264.7 macrophages cause an overproduction of IL-1β, TNF-α, IL-6 and KC that closely reflects the pathogenesis of ALI (Hou et al., 2018). CT-133 pretreatment noticeably inhibits this LPS- and PGD2-induced overexpression. We also find that macrophage number is much lower in the CT-133-treated (30 mg/kg) group than in the LPS treated group, suggesting that CRTH2 antagonism alters the macrophage influx and alleviates the damage due to the pro-inflammatory mediators in the LPS-induced mouse ALI model. NF-κB plays a pivotal role in the transcriptional regulation of various inflammation-related genes. Elevated NF-kB levels have been reported in LPS-induced ALI murine models (Xu et al., 2011; Yu et al., 2013), and pharmacological inhibition of the NF-kB pathway significantly decreases airway inflammation by inhibiting the MPO section, pulmonary vascular permeability and pro-inflammatory mediator production (Feng et al., 2015; Nathens et al., 1997). Inhibition of NF-κB activation also suppresses the pathological changes in murine ALI models (Oishi et al., 2012). Accumulated evidence has revealed that NF-κB activation is accompanied by phosphorylation and degradation of IκBα, which ultimately promotes P65 phosphorylation and translocation into the nucleus, where it drives expression of specific target genes (Scott et al., 1993). In our study, we find that an LPS challenge significantly increased IκBα and P65 phosphorylation in the lung tissues and RAW264.7 macrophages, whereas CT-133 treatment dose-dependently and markedly inhibits the activation of NF-κB signalling. Taken together, these findings indicate that the inhibition of the NF-kB pathway plays a role in the protection of CT-133 against LPS-induced ALI.
    Introduction Acute lung injury (ALI) and its severe demonstration, acute respiratory distress syndrome (ARDS), are life-threatening clinical syndromes. The most characteristic pathological features of ALI/ARDS include increased pulmonary vascular permeability and edema, inappropriate recruitment of alveolar macrophages and pulmonary neutrophils, uncontrolled secretion of pro-inflammatory mediators, surfactant dysfunction, impaired gas exchange, and subsequent respiratory failure owing to progressive and refractory hypoxemia [1]. Despite decades of extensive research, ALI/ARDS remain a major cause of morbidity and mortality in critically ill patients, with 10% prevalence in intensive care units (ICU) and 40–46% mortality [2], and no definite pharmacological agent is available yet [3]. However, scarce pharmacological options for ALI present an unrelenting challenge in the field of drug development. Therefore, new therapeutic approaches are needed to improve the drug development for ALI.