Bradykinin system is involved in endometriosis-related pain through endothelin-1 production.

Endometriosis is a gynaecological disease exhibiting severe pelvic pain, but the mechanism of pain production remains unknown. Bradykinin (BK) is known as an inflammatory mediator, and shows elevated levels in inflammatory diseases such as rheumatoid arthritis. In the present study, we evaluated whether BK is involved in endometriosis-related pain. Endometriotic lesions were used for immunohistochemistry. Primary cultures of endometriotic stromal cells (ESC) were stimulated with IL-1β and/or BK. Quantitative RT-PCR was used to evaluate the mRNA expressions of BK receptors (BKR) and endothelin-1 in ESC. The concentration of endothelin-1 in cystic fluid of endometrioma or non-endometrioma was measured with ELISA. The conditioned medium of ESC stimulated with IL-1β and/or BK was injected intraplantarly in mice, and evaluated whether pain-related licking behaviour was elicited. The expressions of BK and BKR in endometriotic lesions were observed by immunohistochemistry. In vitro experiments showed that IL-1β induced BKR-B1 and B2 on ESC. Activation of these receptors by BK significantly induced endothelin-1 expression in ESC, which was negated completely by HOE-140, a BKR-B2 antagonist. The cystic fluid of endometrioma contained higher amount of endothelin-1 compared to non-endometrioma. Intraplantar injection of the conditioned medium of ESC treated with IL-1β and BK significantly induced licking behaviour, which was suppressed with BQ-123, an endothelin type-A receptor antagonist. The present study demonstrated the presence and the function of the BK axis in endometriosis, and established a potential new therapy target for endometriosis-related pain. The present study demonstrated (1) the presence and the function of the BK system in endometriosis, (2) activation of BKR induced endothelin-1 in endometriotic lesion and (3) blocking endothelin-1 was effective to decrease pain.

Yoshino O ，Yamada-Nomoto K ，Kobayashi M ，Andoh T ，Hongo M ，Ono Y ，Hasegawa-Idemitsu A ，Sakai A ，Osuga Y ，Saito S ... -  《-》

Expression of Nerve Injury-Induced Protein1 (Ninj1) in Endometriosis.

Miyashita M ，Koga K ，Takeuchi A ，Makabe T ，Taguchi A ，Urata Y ，Izumi G ，Takamura M ，Harada M ，Hirata T ，Hirota Y ，Wada-Hiraike O ，Yoshino O ，Fujii T ，Osuga Y ... -  《-》

Trabecular meshwork bradykinin receptors: mRNA levels, immunohistochemical visualization, signaling processes pharmacology, and linkage to IOP reduction.

Sharif NA ，Katoli P ，Kelly CR ，Li L ，Xu S ，Wang Y ，Klekar L ，Earnest D ，Yacoub S ，Hamilton G ，Jacobson N ，Shepard AR ，Ellis D ... -  《-》

Bradykinin upregulates IL-8 production in human gingival fibroblasts stimulated by interleukin-1beta and tumor necrosis factor alpha.

Brunius G ，Domeij H ，Gustavsson A ，Yucel-Lindberg T ... -  《regulatory peptides》

Bradykinin B2 receptors play a neuroprotective role in Hypoxia/reoxygenation injury related to pyroptosis pathway.

Kinins are pro-inflammatory peptides that mediate numerous vascular and pain responses in tissue injury. Kinins exert their biological functions via two G-protein-coupled receptors: Bradykinin 1 Receptor (B1R) and Bradykinin 2 Receptor (B2R). We previously demonstrated the up-regulation of B2R after Hypoxia/Reoxygenation (H/R) injury in primary cultured cortical neurons. However, the role of B2R in inflammasome-induced pyroptosis remains unknown. We induced H/R neuronal injury in primary cultured cortical neurons harvested from embryonic day 17 brains. Next, we examined the neuroprotective function of B2R in H/R-induced neuronal apoptosis or necrosis using an annexin V FITC/Propidium Iodide (PI) double-staining technique. The pyroptosis signaling cascade, including caspase-1, IL-1β and IL-18 levels and Cleaved Gasdermin D (GSDMD) expression was examined by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blotting to explore the underlying molecular mechanism. H/R injury significantly increased B2R protein expression (P<0.05) as well as the percentage of early apoptotic and necrotic or late apoptotic neurons as verified by the annexin V FITC/PI flow cytometric analysis. Bradykinin (BK), a specific B2R agonist, caused a significant decrease in apoptotic neuronal death after H/R injury, while HOE140, a specific B2R antagonist, markedly reduced the neuroprotective effect of B2R. Following H/R injury, BK downregulated the caspase-1, IL-1β and IL-18 levels (P<0.01). In contrast, pretreatment with HOE140 significantly increased caspase-1, IL-1β, and IL-18 levels (P<0.01). Further analysis revealed that GSDMD, a key executioner of pyroptosis, is a target for B2R-mediated inhibition of neuronal pyroptosis. Cleaved GSDMD expression was significantly inhibited by BK pretreatment and significantly enhanced by HOE140 pretreatment (P<0.01). These results indicate that activation of B2R plays an important role in pyroptosis mediated by H/R injury.

Tang M ，Li X ，Liu P ，Wang J ，He F ，Zhu X ... -  《-》