Endometritis is the most common bovine uterine disease following parturition. The role of prostaglandin E₂ (PGE₂) in the regulation of endometrial inflammation and repair is well understood. Excess PGE₂ is also generated in multiple inflammatory diseases, including endometritis. However, it remains unclear whether PGE₂ is associated with pathogen-induced inflammatory damage to the endometrium. To clarify the role of PGE₂ in pathogen-induced inflammatory damage, this study evaluated the production of PGE₂, inflammatory factors, and damage-associated molecular patterns (DAMPs) in cultured Escherichia coli-infected bovine endometrial tissue. PGE₂ production was significantly higher in E. coli-infected tissue, and in E. coli-infected tissue treated with 15-prostaglandin dehydrogenase (15-PGDH) inhibitors, as compared to uninfected tissue. Phospholipase A2 (PLA2), cyclooxygenase-2 (COX-2), and microsomal prostaglandin E synthase-1 (mPGES-1) were also upregulated in E. coli-infected tissue, while concentrations of arachidonic acid (AA), leukotrienes, DAMPs, and other proinflammatory factors increased. The accumulation of PGE₂ clearly damaged the cultured tissue. Treatment with the COX-2, mPGES-1, EP4, and protein kinase A (PKA) inhibitors decreased the production of PGE₂, inflammatory factors, and DAMPs, simultaneously alleviating the E. coli-induced endometrial tissue damage. Therefore, the PGE₂ that was generated by COX-2 and mPGES-1 accumulated, and this pathogenic PGE₂ increased inflammatory damage by upregulating inflammatory factors and DAMPs in E. coli-infected bovine endometrial tissue. This upregulation of inflammatory factors and DAMPs might be regulated by the EP₄-PKA signaling pathway.

Summary Sentence

Escherichia coli infection of the bovine uterine explants activated the COX2-mPGES-PGE2 pathway, leading to the accumulation of PGE2, which induced proinflammatory cytokines IL-beta, IL-6, IL-8, TNF-alpha expression and tissue injure via PGE2-EP4-PKA pathway.