Abstract
BackgroundPathogens of otitis media (OM) induce inflammatory responses in the middle ear (ME), characterized by mucosal hyperplasia, leukocyte infiltration, and inflammatory mediators, including arachidonic acid metabolites. We studied the role of the eicosanoid leukotriene B4 (LTB4) in OM.MethodsExpression of LTB4-related genes was evaluated by gene array and single-cell RNA-Seq in MEs infected with nontypeable Haemophilus influenzae (NTHi). An inhibitor of LTB4 receptor 1 (i.e. U75302) was also used to block LTB4 responses.ResultsME expression of LTB4-related genes was observed by gene arrays and scRNA-Seq. However, not all genes involved in LTB4 generation occurred in any one specific cell type. Moreover, LTB4 receptor inhibition significantly reduced mucosal hyperplasia and virtually eliminated leukocyte infiltration.ConclusionsME expression of LTB4-related genes suggest a functional role in OM disease. The fact that LTB4-generation is spread across different cell types is consistent with a transcellular pathway of eicosanoid biosynthesis involving cell-to-cell signaling as well as transfer of biosynthetic intermediates between cells. The dramatic reduction in ME leukocyte infiltration caused by U75302 indicates that LTB4 plays a major role in ME inflammatory cell recruitment, acting via the LTB4R1 receptor. Given that there are many other chemotactic factors that occur in the ME during OM, the ability of LTB4 to activate leukocytes and stimulate their extravasation may explain the effects of inhibition. Reduction in mucosal hyperplasia due to U75302 administration may be secondary to the reduction in leukocytes since LTB4R1 is not expressed by mucosal epithelial or stromal cells. The results suggest that LTB4 receptor antagonists could be useful in treating OM.
Highlights
Otitis media (OM) is the most prevalent disease of childhood (Casselbrant et al, 1993)
The WHO estimates that undertreated OM, leading to chronic suppurative OM (CSOM), leads to 30,000 deaths per year due to meningitis
As assessed by cRNA probe hybridization to gene arrays, several genes involved in leukotriene B4 (LTB4) production and sensing were significantly upregulated following nontypeable Haemophilus influenzae (NTHi) inoculation of the middle ear (ME) (Figure 2A)
Summary
Otitis media (OM) is the most prevalent disease of childhood (Casselbrant et al, 1993). OM peaks between the ages of 6 months and two years (Pichichero, 2016), which is a critical period for the development of speech and language. In the US, OM causes more pediatrician visits, antibiotic prescriptions, and surgeries than any other condition for children under 5 years of age (Rovers et al, 2008), at a cost estimated at $5 billion per year (Rosenfeld and Bluestone, 2003; Klein, 2000; Tong et al, 2018). WHO estimates that CSOM is responsible for half of the world’s burden of handicapping hearing loss, more than 275 million cases (WHO, 2004; Leach et al, 2020; WHO, 2020). We studied the role of the eicosanoid leukotriene B4 (LTB4) in OM
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