Inhibition of Plasmin Protects Against Colitis in Mice by Suppressing Matrix Metalloproteinase 9–Mediated Cytokine Release From Myeloid Cells

Munakata, Shinya; Tashiro, Yoshihiko; Nishida, Chiemi; Sato, Aki; Komiyama, Hiromitsu; Shimazu, Hiroshi; Dhahri, Douaa; Salama, Yousef; Eiamboonsert, Salita; Takeda, Kazuyoshi; Yagita, Hideo; Tsuda, Yuko; Okada, Yoshio; Nakauchi, Hiromitsu; Sakamoto, Kazuhiro; Heissig, Beate; Hattori, Koichi

doi:10.1053/j.gastro.2014.12.001

Cited by 43 publications

(27 citation statements)

References 38 publications

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“…Among the latter, MMP-9 is known to play an important role as a promotion factor during cancer transposition and plays an indispensable role in hematogenous cell migration in vivo. The expression of MMP-9, which is closely associated with the activity of macrophages, is correlated with the expression of CD68 (a macrophage-specific marker), and an increase in MMP-9 causes a proliferation and migration of macrophages (19). In the present study, we observed an increase in MMP-9 expression and macrophage proliferation/migration (Fig.…”

Section: Discussionsupporting

confidence: 73%

Tranexamic Acid Ameliorates Nonmelanoma Skin Cancer Induced by Long‐term Ultraviolet A Irradiation

Hiramoto

Yamate

Sugiyama

et al. 2018

Photochem & Photobiology

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To date, there have been no treatments developed to ameliorate nonmelanoma skin cancer induced by long‐term exposure to ultraviolet A (UVA) irradiation. In this study, we examined the effects of tranexamic acid (trans‐4‐aminomethyl cyclohexanecarboxylic acid) on long‐term UVA‐induced skin cancer. We exposed the dorsal skin of male hairless mice to UVA at a dose of 110 kJ m−2 using an FL20SBLB‐A lamp three times weekly for 15 weeks after application of 7,12‐dimethylbenz [a] anthracene (DMBA). During the experimental period, the mice were administered tranexamic acid (750 mg kg−1 day−1) three times weekly. We found that cancer development was ameliorated by administration of tranexamic acid. Furthermore, tranexamic acid treatment was observed to suppress increases in the plasma levels of matrix metalloproteinase‐9 and interleukin (IL)‐6, and skin expression of plasmin, CC chemokine 2, macrophages, signal transducer and activator of transcription (STAT)3, cyclin D and vascular endothelial growth factor (VEGF)‐A that occurred in mice subjected to long‐term UVA irradiation. These results indicated that the nonmelanoma skin cancer induced by DMBA+UVA long‐term irradiation is ameliorated by tranexamic acid through regulation of the plasmin/macrophage/IL‐6/STAT3/cyclin D signal transmission pathway. In addition, this ameliorative effect against skin cancer may be mediated via inhibition of the IL‐6‐induced expression of VEGF‐A.

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Section: Discussionsupporting

confidence: 73%

Tranexamic Acid Ameliorates Nonmelanoma Skin Cancer Induced by Long‐term Ultraviolet A Irradiation

Hiramoto

Yamate

Sugiyama

et al. 2018

Photochem & Photobiology

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“…Human omental tissue mesothelial cells produce large amounts of tPA in vitro , together with PAI‐1 and PAI‐2 (23). More PAI‐1 was released from mesothelial cells that were isolated from mice with intra‐abdominal adhesion compared with control mice ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Plasminogen activator inhibitor‐1 regulates macrophage‐dependent postoperative adhesion by enhancing EGF‐HER1 signaling in mice

et al. 2017

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Adhesive small bowel obstruction remains a common problem for surgeons. After surgery, platelet aggregation contributes to coagulation cascade and fibrin clot formation. With clotting, fibrin degradation is simultaneously enhanced, driven by tissue plasminogen activator-mediated cleavage of plasminogen to form plasmin. The aim of this study was to investigate the cellular events and proteolytic responses that surround plasminogen activator inhibitor (PAI-1; ) inhibition of postoperative adhesion. Peritoneal adhesion was induced by gauze deposition in the abdominal cavity in C57BL/6 mice and those that were deficient in fibrinolytic factors, such as and In addition, C57BL/6 mice were treated with the novel PAI-1 inhibitor, TM5275. Some animals were treated with clodronate to deplete macrophages. Epidermal growth factor (EGF) experiments were performed to understand the role of macrophages and how EGF contributes to adhesion. In the early phase of adhesive small bowel obstruction, increased PAI-1 activity was observed in the peritoneal cavity. Genetic and pharmacologic PAI-1 inhibition prevented progression of adhesion and increased circulating plasmin. Whereas Serpine1 mice showed intra-abdominal bleeding, mice that were treated with TM5275 did not. Mechanistically, PAI-1, in combination with tissue plasminogen activator, served as a chemoattractant for macrophages that, in turn, secreted EGF and up-regulated the receptor, HER1, on peritoneal mesothelial cells, which led to PAI-1 secretion, further fueling the vicious cycle of impaired fibrinolysis at the adhesive site. Controlled inhibition of PAI-1 not only enhanced activation of the fibrinolytic system, but also prevented recruitment of EGF-secreting macrophages. Pharmacologic PAI-1 inhibition ameliorated adhesion formation in a macrophage-dependent manner.-Honjo, K., Munakata, S., Tashiro, Y., Salama, Y., Shimazu, H., Eiamboonsert, S., Dhahri, D., Ichimura, A., Dan, T., Miyata, T., Takeda, K., Sakamoto, K., Hattori, K., Heissig, B. Plasminogen activator inhibitor-1 regulates macrophage-dependent postoperative adhesion by enhancing EGF-HER1 signaling in mice.

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“…As a consequence, the treated mice did not develop colitis. 5 Results from a different mouse model revealed that plasmin and/or MMP-9 inhibition could be a suitable strategy to control the deadly cytokine storm in patients with acute graftversus-host disease. 6 Moreover, enhanced plasminogen activation leading to increased plasmin activity has been linked to cancer invasion and metastasis.…”

Section: ■ Introductionmentioning

confidence: 99%

Optimization of Cyclic Plasmin Inhibitors: From Benzamidines to Benzylamines

et al. 2016

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New macrocyclic plasmin inhibitors based on our previously optimized P2-P3 core segment have been developed. In the first series, the P4 residue was modified, whereas the 4-amidinobenzylamide in P1 position was maintained. The originally used P4 benzylsulfonyl residue could be replaced by various sulfonyl- or urethane-like protecting groups. In the second series, the P1 benzamidine was modified and a strong potency and excellent selectivity was retained by incorporation of p-xylenediamine. Several analogues inhibit plasmin in the subnanomolar range, and their potency against related trypsin-like serine proteases including trypsin itself could be further reduced. Selected derivatives have been tested in a plasma fibrinolysis assay and are more effective than the reference inhibitor aprotinin. The crystal structure of one inhibitor was determined in complex with trypsin. The binding mode reveals a sterical clash of the inhibitor's linker segment with the 99-hairpin loop of trypsin, which is absent in plasmin.

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Inhibition of Plasmin Protects Against Colitis in Mice by Suppressing Matrix Metalloproteinase 9–Mediated Cytokine Release From Myeloid Cells

Cited by 43 publications

References 38 publications

Tranexamic Acid Ameliorates Nonmelanoma Skin Cancer Induced by Long‐term Ultraviolet A Irradiation

Tranexamic Acid Ameliorates Nonmelanoma Skin Cancer Induced by Long‐term Ultraviolet A Irradiation

Plasminogen activator inhibitor‐1 regulates macrophage‐dependent postoperative adhesion by enhancing EGF‐HER1 signaling in mice

Optimization of Cyclic Plasmin Inhibitors: From Benzamidines to Benzylamines

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