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  • These evidence prompted us to investigate the effectiveness


    These evidence prompted us to investigate the effectiveness of CT-133, a newly discovered, well-tolerated, selective and potent CRTH2 antagonist, as a treatment of ALI. CT-133 has shown a potential response in treating chronic obstructive pulmonary disease (COPD), allergic rhinitis and PF-04449913 (Guo, 2015), but it has not been evaluated in LPS-induced ALI models. The present study was designed to explore the protective role of CT-133 in an LPS-induced mouse ALI model and demonstrated that CT-133, a CRTH2 antagonist, suppresses NF-κB signalling to relieve LPS-induced ALI.
    Materials and methods
    Discussion The experimental outcomes presented here are the first to reveal the significant effect of a CRTH2 antagonist on LPS-induced lung injury. CRTH2 antagonism with CT-133 strikingly reduced many of the LPS-induced cardinal features in the mouse ALI model, including neutrophil and macrophage accumulation and pro-inflammatory cytokines and albumin production in BAL fluid, hypoxemia, lung weight coefficient increases, Evans blue exudation into the lungs, lung MPO activity and lung histopathological changes. CT-133 treatment also significantly minimised the in vitro PGD2-induced neutrophil migration and LPS/PGD2-stimulated overexpression of pro-inflammatory cytokines and a chemokine in RAW264.7 macrophages. CT-133 treatment also markedly inhibited the LPS-induced activation of NF-κB at both the in vitro and in vivo levels. Excessive infiltration and accumulation of inflammatory cells, particularly neutrophils, in both alveolar and interstitial spaces is one of the pivotal pathological hallmarks of lung injury (Li et al., 2016; Zhou et al., 2011). A rapid and appropriate neutrophil influx is crucial for clearance of alveolar pathogens and debris; however, neutrophilia may contribute to extensive lung inflammation and substantially increased alveolar-capillary membrane permeability due to the release of several toxic mediators from the neutrophils (Bhattacharya and Matthay, 2013; Chignard and Balloy, 2000). Notably, the finding of increased numbers of neutrophils in BAL fluid is closely related to the severity of lung injury (Abraham, 2003; Grommes and Soehnlein, 2011), while the severity of LPS-induced lung injury has been reduced by neutrophil depletion in mice (Chignard and Balloy, 2000; Li et al., 2016). In LPS-induced murine models, PGD2 is a critical mediator of macrophage migration (Tajima et al., 2008), and activated PGD2/CRTH2 receptors on macrophages orchestrate neutrophil recruitment into the lung, augmenting the disease severity (Jandl et al., 2016). CRTH2 acts as a critical regulator of neutrophil migration (Ishii et al., 2012), because CRTH2 agonists trigger neutrophil migration (Shichijo et al., 2003), while selective CRTH2 antagonists inhibit neutrophil trafficking into the lung (Stebbins et al., 2010). Similarly, genetic ablation of CRTH2 suppresses neutrophil migration in sepsis models (Ishii et al., 2012) and increases the survival rate in ALI models (Suzuki et al., 2016). In the present study, we find that intratracheal instillation of LPS strikingly increases inflammatory cell counts, neutrophil infiltration and MPO activity in the lungs, whereas CT-133 treatment markedly ameliorates the LPS-induced increases in inflammatory cell and neutrophil numbers, reduced the MPO activity and lessened the lung hypoxemia. These outcomes suggest that the protective effects of CT-133 might be due to an inhibition of neutrophil migration and a reduction in pulmonary vascular permeability, via a CRTH2 receptor blockade. Our further investigation confirms that CT-133 blocks PGD2-induced neutrophil migration in vitro, and minimises the LPS-induced accumulation of albumin in BAL fluid, Evans blue accumulation in lungs and pulmonary oedema. Lung histological examinations and lung injury scores also show that CT-133 attenuates the LPS-induced alveolar wall damage, neutrophil infiltration and lung tissue injury.