Supported by the Austrian Science Fund
Supported by the Austrian Science Fund FWF (grant P22521-B18 to A.H.) and the Austrian National Bank (grant 14263 to A.H.). K.J. was funded by the PhD Program DK-MOLIN (FWF-W1241).
Introduction Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), a more severe form of ALI, are devastating clinical syndromes characterised by alveolar-capillary membrane hyper-permeability, oedema, infiltration of neutrophils into interstitial spaces, neutrophil-derived inflammation, and dysfunction of surfactant and involved cells, including endothelial cells, epithelial FPH2 and macrophages (Wheeler and Bernard, 2007). A recent global observational study revealed increased mortality in patients with ALI/ARDS (Bellani et al., 2016), while surviving patients are at high risk of depression, cognitive decline, persistent skeletal-muscle weakness and post-traumatic stress disorder (Herridge et al., 2016). Despite decades of widespread research, no distinct pharmacological agent is presently available to manage ALI (Hussain et al., 2018). Therefore, novel pharmacological approaches are urgently needed. ALI can be induced experimentally by lipopolysaccharide (LPS), a ligand of Toll-like receptor 4 (TLR4) and the primary stimulus of macrophage activation. LPS treatment immediately activates the TLR4-linked nuclear factor kappa-B (NF-κB) signalling pathway (Yang et al., 2017). Generally, NF-κB, a heterodimer composed primarily of P65 and P50, stays in the cytoplasm as an inactive form due to the action of an inhibitory protein IκB, especially IκBα (Karin, 1999; Karin and Ben-Neriah, 2000). Upon inflammatory stimuli such as LPS, IκB is phosphorylated by IκB kinase (IKK) and degraded, thereby releasing NF-κB to translocate into the nucleus, where NF-κB induces the transcription of several pro-inflammatory cytokines, such as tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, IL-8, and other inflammatory mediators, such as prostaglandin (PG) D2/E2 and nitric oxide (NO) (Bhatia and Moochhala, 2004; Matthay et al., 2012). LPS also stimulates macrophage migration via the chemoattractants PGD2 and PGE2 (Tajima et al., 2008) that orchestrate neutrophilic infiltration into the lung (Dhaliwal et al., 2012). The activated neutrophils provoke further lung inflammation (Li et al., 2016; Zhou et al., 2011). Accumulated evidence now indicates that targeting of NF-κB not only alleviates the pro-inflammatory cytokine production but also suppresses the pulmonary oedema and influx of neutrophils, which are key characteristics of ALI (Everhart et al., 2006; Yang et al., 2012). Therefore, LPS-induced ALI mouse models are appropriate for the evaluation of pharmacological effects of therapeutic compounds, because the lung injury symptoms observed in LPS-induced ALI mice overall are consistent with those observed in patients with ARDS. Emerging evidence reveals that PGD2, which is mainly produced from allergen-stimulated mast cells and Th2 lymphocytes, has a crucial role in mediating airway inflammation. PGD2 has diverse functions, including activation of the D-type prostanoid receptors (DPs) DP1 and DP2, DP2 is also known as chemoattractant receptor-homologous molecules expressed on Th2 (CRTH2) cells. Activation of PGD2/CRTH2 receptors on macrophages promotes neutrophil migration and their survival in the lung, as well as augmenting the disease severity through excessive production of pro-inflammatory cytokines and subsequent neutrophil activation. Consequently, antagonism of CRTH2 ameliorates the alveolar influx of neutrophils, thereby lessening the disease severity (Jandl et al., 2016). Furthermore, CRTH2-knockout mice have shown an increased survival rate and decreased levels of pro-inflammatory cytokines and total protein in the lungs in response to LPS injection when compared to control mice (Suzuki et al., 2016). CRTH2 antagonists have been effective in treating eosinophilic esophagitis (Straumann et al., 2013), allergic rhinitis (Krug et al., 2014) and asthma (Gonem et al., 2016; Singh et al., 2013).