Mucin overproduction is a hallmark of otitis media (OM). Streptococcus pneumoniae is one of the most common bacterial pathogens causing OM. Mucin MUC5AC plays an important role in mucociliary clearance of bacterial pathogens. However, if uncontrolled, excessive mucus contributes significantly to conductive hearing loss. Currently, there is a lack of effective therapeutic agents that suppress mucus overproduction. In this study, we show that a currently existing antistroke drug, vinpocetine, a derivative of the alkaloid vincamine, inhibited S. pneumoniae–induced mucin MUC5AC upregulation in cultured middle ear epithelial cells and in the middle ear of mice. Moreover, vinpocetine inhibited MUC5AC upregulation by inhibiting the MAPK ERK pathway in an MKP-1–dependent manner. Importantly, ototopical administration of vinpocetine postinfection inhibited MUC5AC expression and middle ear inflammation induced by S. pneumoniae and reduced hearing loss and pneumococcal loads in a well-established mouse model of OM. Thus, these studies identified vinpocetine as a potential therapeutic agent for inhibiting mucus production in the pathogenesis of OM.

Appropriate production of mucous plays a critical role in host innate mucosal defenses against infection. However, if uncontrolled, excessive mucous may be detrimental to the host. Mucous production thus must be tightly regulated. In the present study, we investigate the role of RIP-2 in regulating nontypeable Haemophilus influenzae (NTHi)-induced up-regulation of mucin MUC5AC expression. We show that RIP-2 is a negative regulator of MUC5AC, whereas MAP kinase JNK acts as a positive regulator for MUC5AC induction by NTHi. Our studies unveil a novel role for RIP-2 in controlling mucous production in upper respiratory disease and may shed light on the identification of new therapeutic targets.