Vinpocetine Inhibits Streptococcus pneumoniae–Induced Upregulation of Mucin MUC5AC Expression via Induction of MKP-1 Phosphatase in the Pathogenesis of Otitis Media

Abstract

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.

Receptor Interacting Protein-2 acts as negative regulator for nontypeable Haemophilus influenzae-induced mucin MUC5AC expression

“…Anesthetized mice were inoculated with NTHi at a concentration of 1 × 10 7 CFU per mouse or saline as control [2]. The inoculated mice were sacrificed at 6 and 12 h postinoculation.…”

“…As previously described [2], formalin-fixed paraffin-embedded mouse middle ear tissues were sectioned (4 µm), and then stained with hematoxylin and eosin (H&E) to visualize inflammatory responses and pathological changes in the middle ear. Images of stained cells and tissue sections were recorded with light microscopy system (Carl Zeiss).…”

“…Total RNA extraction and RT-qPCR were performed as previously described [2][3][4][12][13][14][15][16][17]. The relative quantities of mRNAs were determined by using the comparative Ct method and were normalized by using human cyclophilin for in vitro or mouse glyceraldehyde-3-phosphate dehydrogenase (GAPDH) for in vivo as endogenous controls.…”

“…Mucins are a family of high molecular weight glycoproteins secreted by goblet cells in mucosal tissues. There are more than 20 known mucins, twelve of which have been found in the respiratory tract [2]. Mucin 5AC (MUC5AC) is known to be one of the major mucins produced during upper respiratory infections, including otitis media (OM).…”

“…Mucin 5AC (MUC5AC) is known to be one of the major mucins produced during upper respiratory infections, including otitis media (OM). While appropriate mucous production is protective for the host, excessive mucous production can be deleterious [1][2][3][4]. In fact, thick mucous and neutrophil nets can create a biofilmlike environment for nontypeable Haemophilus influenzae (NTHi), one of the major bacterial pathogens of OM and chronic obstructive pulmonary disease (COPD).…”