Protease activated‐receptor 4 activation as a model of persistent bladder pain: Essential role of macrophage migration inhibitory factor and high mobility group box 1

Ma, Fei; Hunt, David E.; Leng, Lin; Bucala, Richard; Meyer-Siegler, Katherine L.; Vera, Pedro L.

doi:10.1111/iju.13778

Cited by 9 publications

(23 citation statements)

References 27 publications

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“…Abdominal mechanical hypersensitivity was elicited after repeated PAR4-treatment (Fig 2; red arrows indicated intravesical treatments) as we reported earlier [14]. Spinal administration of neutralizing MIF mAb partially reversed persistent bladder pain at 1 hour post-intrathecal injection (0.074 ± 0.017 vs. 0 hour 0.002 ± 0.001, p < 0.01) and the effect peaked at 2 hours (0.141 ± 0.02, p < 0.001).…”

Section: Persistent Bladder Pain Alleviation By Spinal Mif and Hmgb1 supporting

confidence: 77%

“…edema; infiltrating cells) [9,10]. We extended our findings using a mouse model of persistent bladder pain that showed the abdominal mechanical hypersensitivity (referred bladder pain) persisted for 5 days after the last bladder stimulus and in absence of bladder injury or bladder inflammation [14]. Mechanisms other than bladder effects may participate in this model of persistent bladder pain.…”

Section: Discussionsupporting

confidence: 60%

“…Repeated intravesical instillation of PAR4 to induce persistent bladder pain was previously described [14]. Briefly, PAR4-AP or PAR4-scrambled peptide as control (100 μM in PBS; 150 μl; Peptides International, Louisville, KY) were instilled into the mouse bladder lumen under isoflurane anesthesia and held for 1 hour.…”

Section: Abdominal Mechanical Hypersensitivity Testmentioning

confidence: 99%

“…Intravesical instillation occurred on day 0, 2 and 4 for a total of three intravesical instillations. Abdominal mechanical hypersensitivity was tested in mice by recording 50% mechanical threshold as described [14]. Briefly, mechanical threshold was measured with eight von Frey fibers (0.008, 0.02, 0.07, 0.16, 0.4, 1.0, 2.0 and 6.0 g).…”

Section: Abdominal Mechanical Hypersensitivity Testmentioning

confidence: 99%

“…Recently, we developed a persistent bladder pain model by repeated intravesical installation of PAR4 (3x, 48 hours apart) and bladder pain was maintained 5 days after last intravesical treatment [14]. No overt histological signs of inflammation were shown in the afflicted bladders indicating that the bladder pain maintenance is independent of direct bladder injury and that bladder pain persisted after bladder injury resolution.…”

Section: Introductionmentioning

confidence: 99%

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Spinal macrophage migration inhibitory factor and high mobility group box 1 mediate persistent bladder pain

Meyer-Siegler

Leng

et al. 2019

Neuroscience Letters

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Repeated intravesical PAR4 (protease activated receptor 4) activation elicits persistent bladder pain lasting 5 days after the last treatment. Persistent bladder pain was fully reversed by a systemic HMGB1 (high mobility box 1) inhibitor while a MIF (macrophage migration inhibitory factor) antagonist partly reversed it. Since there is growing evidence that spinal MIF and HMGB1 mediate inflammatory and neuropathic pain we examined whether there were spinal changes occurring during persistent bladder pain that may be responsible for maintaining bladder pain. In addition, we tested whether we could modulate persistent bladder pain with spinal MIF or HMGB1 antagonists. Persistent bladder pain was elicited in female C57 mice by repeated (3x) intravesical instillation of PAR4-activating peptide while control animals received scramble peptide treatment. On day 4, spinal cord (L6-S1) changes in c-fos (non-specific marker of spinal activation) was assessed with immunofluorescence while MIF and HMGB1 were assessed with immunofluorescence, western blotting and real-time PCR. On day 7, mice received an intrathecal injection of a neutralizing MIF monoclonal antibody (15 μg in 5 μl PBS) or a HMGB1 inhibitor glycyrrhizin (25 μg in 5 μl of 5 % alcohol in PBS) and abdominal mechanical threshold was tested. On day 9, mice were treated with vehicle or control and abdominal mechanical threshold was tested. Immunofluorescence showed that c-fos and MIF in the dorsal horn, dorsal grey commissure and intermediolateral areas significantly increased in PAR4-treated mice while HMGB1 was decreased. In addition, intrathecal treatment with MIF neutralizing mAb or glycyrrhizin significantly alleviated abdominal mechanical hypersensitivity at 1 and 2 hours and the analgesic *

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Section: Persistent Bladder Pain Alleviation By Spinal Mif and Hmgb1 supporting

confidence: 77%

Section: Discussionsupporting

confidence: 60%

Section: Abdominal Mechanical Hypersensitivity Testmentioning

confidence: 99%

Section: Abdominal Mechanical Hypersensitivity Testmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Spinal macrophage migration inhibitory factor and high mobility group box 1 mediate persistent bladder pain

Meyer-Siegler

Leng

et al. 2019

Neuroscience Letters

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Lumbosacral spinal proteomic changes during PAR4-induced persistent bladder pain

Ye,

Agalave,

et al. 2024

Neuroscience Letters

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The Yin‐Yang roles of protease‐activated receptors in inflammatory signalling and diseases

Xin

et al. 2022

The FEBS Journal

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Inflammatory diseases have become increasingly prevalent throughout the world. Coronavirus disease 2019 , which has recently become pandemic, also exhibits hyperinflammation and cytokine release syndrome. To address inflammation-related diseases, numerous molecular targets have been explored in preclinical studies and clinical trials. Among them, the protease-activated receptors (PARs) that belong to G protein-coupled receptors are one of the most popular classes of drug targets, participating in inflammatory signalling and diseases. PARs activation can trigger downstream intracellular signalling to modulate a variety of inflammatory responses in multiple systems, including nervous, respiratory, digestive, circulatory, urinary and immune systems. Importantly, there are the Yin-Yang effects, comprising anti-and pro-inflammatory roles, of PARs activation in different types of inflammations, and these are context-dependent. Alternatively, it was recently revealed that PARs not only modulate inflammatory-related tumour progression, but also participate in inflammatory cytokine release related to COVID-19 via direct interaction with severe acute respiratory syndrome coronavirus 2 protein, suggesting that PARs also participate in other diseases via inflammatory responses. In this review, we renew and discuss the findings of PARs as molecular targets for treating inflammatory diseases, highlighting the novel roles of PARs and facilitating a better understanding of their designated values in the specific inflammatory environment.

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Protease activated‐receptor 4 activation as a model of persistent bladder pain: Essential role of macrophage migration inhibitory factor and high mobility group box 1

Abstract: Repeated intravesical protease activated receptor 4 instillations produce persistent bladder pain without inflammation. Macrophage migration inhibitory factor and high mobility group box 1 are possible effective target molecules for bladder pain alleviation.

Cited by 9 publications

References 27 publications

Spinal macrophage migration inhibitory factor and high mobility group box 1 mediate persistent bladder pain

Spinal macrophage migration inhibitory factor and high mobility group box 1 mediate persistent bladder pain

Lumbosacral spinal proteomic changes during PAR4-induced persistent bladder pain

The Yin‐Yang roles of protease‐activated receptors in inflammatory signalling and diseases

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