S-Carboxymethylcysteine inhibits adherence of Streptococcus pneumoniae to human alveolar epithelial cells

Abstract

Streptococcus pneumoniae is a major pathogen of respiratory infections that utilizes platelet-activating factor receptor (PAFR) for firm adherence to host cells. The mucolytic agent S-carboxymethylcysteine (S-CMC) has been shown to exert inhibitory effects against infection by several respiratory pathogens including S. pneumoniae in vitro and in vivo. Moreover, clinical studies have implicated the benefits of S-CMC in preventing exacerbation of chronic obstructive pulmonary disease, which is considered to be related to respiratory infections. In this study, to assess whether the potency of S-CMC is attributable to inhibition of pneumococcal adherence to host cells, an alveolar epithelial cell line stimulated with interleukin-1a was used as a model of inflamed epithelial cells. Despite upregulation of PAFR by inflammatory activation, treatment with S-CMC efficiently inhibited pneumococcal adherence to host epithelial cells. In order to gain insight into the inhibitory mechanism, the effects of S-CMC on PAFR expression were also investigated. Following treatment with S-CMC, PAFR expression was reduced at both mRNA and post-transcriptional levels. Interestingly, S-CMC was also effective in inhibiting pneumococcal adherence to cells transfected with PAFR small interfering RNAs. These results indicate S-CMC as a probable inhibitor targeting numerous epithelial receptors that interact with S. pneumoniae. INTRODUCTIONStreptococcus pneumoniae is a major cause of communityacquired pneumonia, sinusitis and otitis media, and is also associated with acute exacerbations of chronic obstructive pulmonary disease (COPD) (Miravitlles et al., 1999). Among the numerous pneumococcal adherence mechanisms responsible for causing diseases, phosphorylcholine binds specifically to platelet-activating factor receptor (PAFR) expressed on the surface of airway epithelial cells (Cundell et al., 1995(Cundell et al., , 1996Fischer, 2000). Previous in vivo experiments demonstrated that PAFR-deficient mice were less likely to develop invasive disease or had improved host defence during pneumococcal infection (Rijneveld et al., 2004). Therefore, the interaction between PAFR and phosphorylcholine plays a crucial role in the pathogenesis of pneumococcal disease.The mucolytic agent S-carboxymethylcysteine (S-CMC) is widely used as an expectorant in Europe and Asia for the treatment of respiratory diseases with phlegm production. Administration of S-CMC is also effective for COPD patients in terms of reductions in symptom exacerbation and improvements in quality of life (Zheng et al., 2008). It is generally accepted that bacterial colonization is a determinant for COPD exacerbation. Hence, it has been speculated that the potency of S-CMC against respiratory pathogens, including S. pneumoniae (Cakan et al., 2003;Suer et al., 2008), Moraxella catarrhalis (Zheng et al., 1999) and non-typable Haemophilus influenzae (Ndour et al., 2001), contributes to a reduction in episodes of respiratory infection in COPD patients. However, the mechanism by which S-C...

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