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  • Injurious effects of cigarette smoke CS on


    Injurious effects of cigarette smoke (CS) on human health are progressively being acknowledged both in animal and human studies. CS is a highly complex mixture that contains substantive amounts of toxic oxidants, nitric oxide, organic compounds, free radicals and microbial cell components including bacterial lipopolysaccharide (LPS) [4]. CS increases susceptibility to the development of ALI/ARDS in critically ill patients [[5], [6], [7]]. CS exposure modifies the trafficking and function of alveolar macrophages and pulmonary neutrophils [8,9], augments both lung epithelial and endothelial permeability [10,11], and encourages the production of pro-inflammatory cytokines and chemokine [12]; pathways central to the pathogenesis of ALI/ARDS. Nevertheless, CS exposure induces the pulmonary inflammation in animals that are appropriate for the pharmacological evaluation of novel therapeutics for ALI. Prostaglandin (PG) D2, primarily released from mast (-)-Huperzine A australia and to a lesser extent from antigen presenting cells and Th2 lymphocytes, exhibits a critical role in mediating airway inflammation, and exerts its assorted biological actions via D-type prostanoid receptor (DPs), namely DP1 and DP2; later known as chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) [13]. Particularly, CS increases the absolute number of mast cells in smokers [14,15], and PGD2 is one of the predominant product released from CS-activated mast cells [16,17]. Elevated levels of PGD2 [18,19] and CRTH2 [20] have been observed in CS-exposed in vivo studies, and a correlation has been noticed between PGD2 concentrations in BALF and CS-induced disease severity [21]. Moreover, activated PGD2/CRTH2 receptors on macrophages promoted the neutrophils recruitment and augmented the disease severity through excessive production of pro-inflammatory cytokines and consequent neutrophil activation [22] while CRTH2 antagonism inhibited the CS-induced inflammation [23,24]. The similar protective effect was shown after genetic deletion of CRTH2 [25]. However, these evidence prompted us to investigate the protective effect of a newly discovered CRTH2 antagonist, CT‑133, against ALI using CS-induced ALI murine models and CSE-stimulated RAW 264.7 macrophages.CT‑133 shows potential response against allergic asthma and rhinitis [26] but to our knowledge, no one has evaluated its protective effect against CS-induced ALI.
    Materials and methods
    Discussion Accumulated epidemiological evidence has revealed that both active and passive CS exposure enhance vulnerability to ALI/ARDS development [5,7]. Excessive influx of inflammatory cells, particularly macrophages and neutrophils, is an important pathological hallmark of CS-induced ALI [8,12,34,35]. Under physiological conditions, quick and appropriate macrophage and neutrophil infiltration are imperative for clearance of alveolar debris and pathogens, while CS hinders the phagocytic abilities of macrophage [36,37] and neutrophils [38] as well as disrupts the pulmonary vascular permeability [11,39,40]. Importantly, PGD2, released from CS-activated mast cells [16,17], was found to be involved in arbitrating macrophage migration in CS-induced lung injury models [23] and activated PGD2/CRTH2 receptors on macrophages orchestrate neutrophils recruitment into the lung [22]. Furthermore, CRTH2 exhibits an important role in neutrophil migration [31] because CRTH2 agonist elicits the neutrophil migration [41], while CRTH2 antagonism [42] or genetic deletion of the CRTH2 receptor [31] improved the impaired neutrophil trafficking into the lung. Importantly, neutrophil infiltration and its activation in lung led to structural changes and bronchial inflammation [43,44]. Hence, many studies have been focused on controlling neutrophilic inflammation in CS-induced lung injury [23,45,46]. Consistent with previous studies, our results demonstrated that CT‑133 dose-dependently and significantly attenuated CS-induced inflammatory cells, macrophage and neutrophils count in BALF and ameliorated lung MPO activity. In addition, lung histological examination and lung injury score also proved that CT‑133 evidently attenuated the severity of inflammation and infiltration of inflammatory cells. Collected outcomes suggest that protective effects of CT‑133 might be due to attenuation of pulmonary vascular permeability and inhibition of neutrophils migration because our further investigations revealed that CT‑133 strikingly minimized CS-induced BALF albumin contents and lung weight coefficient, and blocked PGD2-induced in vitro neutrophils migration.