small molecules

2025-10-01 | Podocyte Cytoskeletal Stabilization Through RhoA-Cofilin Signaling by Suppressing PAI-1

Background: Plasminogen activator inhibitor-1 (PAI-1) is upregulated in various fibrotic kidney diseases. Our previous studies demonstrated that systemic PAI-1 knockout (KO) mitigates glomerulosclerosis and decreases proteinuria by protecting podocytes in chronic kidney disease models. In this study, we investigated whether PAI-1 has direct podocyte effects and explored the underlying mechanisms. Methods: We generated inducible podocyte-specific PAI-1 knockdown mice (PAI-1 KD, PAI-1floxed/podocin Cre+) and wild type control (WT, PAI-1floxed/podocin Cre-). We crossed them with Nphs1-hCD25 mice (Nep25), which express human CD25 specifically in podocytes, and develop primary podocyte injury upon injection with immunotoxin (LMB2). These mice were then assessed at 3 wks after LMB2 for podocyte injury and urine albumin/creatinine ratio (ACR). For in vitro studies, primary podocytes were isolated from WT and PAI-1 KO mice and exposed to puromycin to induce injury. RNA sequencing was performed. RhoA activity was measured using G-LISA assay and phosphorylated cofilin (p-cofilin) levels were quantified by Western Blot. Actin cytoskeleton organization was evaluated by immunofluorescent staining. Results: PAI-1 KD/Nep25 vs Nep25 mice injected with LMB2 showed reduced ACR, less glomerulosclerosis and glomerular collagen IV deposition, with increased WT-1 positive cell density, a marker of mature podocytes. RNA sequencing of cultured PAI-1 KO vs WT podocytes after injury revealed upregulation of 3,387 genes and downregulation of 1,617 genes in the PAI-1 KO. Gene Ontology enrichment and KEGG pathway analyses revealed significant changes in genes involved in cytoskeletal organization. The activity of RhoA, a key regulator of the actin dynamics, was elevated in injured PAI-1 KO compared to WT podocytes. p-cofilin, a downstream target of RhoA that inhibits actin polymerization, was less in PAI-1 KO podocytes, thereby promoting the formation of actin filaments. WT podocytes displayed cell retraction and F-actin disorganization in response to puromycin-induced injury, while PAI-1 KO podocytes maintained intracellular F-actin but had comparable cell retraction. Conclusion: PAI-1 deficiency in podocytes enhances RhoA activity, reduces p-cofilin levels and stabilizes the actin cytoskeleton, thereby improving podocyte structural integrity and protecting against injury. Funding: NIDDK Support

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2025-05-16 | Plasminogen deficiency reduces disease severity and immune responses in enterovirus A71-infected mice.

Enterovirus A71 (EV-A71) is a causative agent of hand, foot, and mouth diseases. EV-A71 infections may result in severe neurological complications in children. Although several receptors or attachment molecules for EV-A71 have been identified, EV-A71 can still infect host cells even after blocking these receptors with antibodies. We have previously identified plasminogen (PLG), a circulating zymogen of plasmin, as a cell membrane-associated EV-A71-interacting glycoprotein. We confirmed that anti-PLG antibodies could reduce the binding of EV-A71 to RD cells as anti-SCARB2 and anti-nucleolin. Knockdown of PLG reduced EV-A71 binding to RD cells, and preincubation of PLG with EV-A71 increased virus binding. Enzyme-linked immunosorbent assay and surface plasmon resonance assays demonstrated the direct binding of PLG to EV-A71. We further evaluated the biological characteristics of EV-A71-infected PLG knockout (heterozygous) and wild-type mice. We found that the clinical scores and mortality of WT mice were higher than those of PLG-knockout mice after EV-A71 infection. The viral loads in the spinal cord of PLG knockout mice were lower than those in WT mice 6 days post-infection. EV-A71-associated cytokines such as IL-1β, IL-6, MCP-1, IL-10, and IFN-γ were investigated. Serum IL-10 and MCP-1 expression were significantly higher in EV-71-infected WT mice than in PLG knockout mice, and MCP-1 may be one of the critical chemokines that induce intense inflammation and chemoattracts leukocytes. Our findings reveal a possible role for PLG in EV-A71 infection/pathogenesis and shed light on developing novel therapeutic approaches and drugs to prevent EV-A71 infection.IMPORTANCEUnderstanding the pathogenesis of enterovirus A71 (EV-A71) for developing novel drugs or therapeutic approaches has always been a significant issue. In this study, we demonstrated the interactions between plasminogen (PLG) and EV-A71, characterized the biological effects of EV-A71-infected PLG knockout mice, and evaluated their immune response. We found that EV-A71 caused more severe tissue damage than PLG knockout mice in skeletal muscle, spinal cord, and brain stem. Higher virus protein was observed in these tissues of WT mice. The reduced clinical scores, mortality, and cytokine expression suggested PLG may be involved in EV-A71 infection-induced cytokine storm. The findings and animal model in the current study provide the new drug target for anti-EV-A71 drug discovery.

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2024-09-25 | PAI-1 Regulates the Cytoskeleton and Intrinsic Stiffness of Vascular Smooth Muscle Cells.

Plasma concentration of PAI-1 (plasminogen activator inhibitor-1) correlates with arterial stiffness. Vascular smooth muscle cells (SMCs) express PAI-1, and the intrinsic stiffness of SMCs is a major determinant of total arterial stiffness. We hypothesized that PAI-1 promotes SMC stiffness by regulating the cytoskeleton and that pharmacological inhibition of PAI-1 decreases SMC and aortic stiffness. PAI-039, a specific inhibitor of PAI-1, and small interfering RNA were used to inhibit PAI-1 expression in cultured human SMCs. Effects of PAI-1 inhibition on SMC stiffness, F-actin (filamentous actin) content, and cytoskeleton-modulating enzymes were assessed. WT (wild-type) and PAI-1-deficient murine SMCs were used to determine PAI-039 specificity. RNA sequencing was performed to determine the effects of PAI-039 on SMC gene expression. In vivo effects of PAI-039 were assessed by aortic pulse wave velocity. PAI-039 significantly reduced intrinsic stiffness of human SMCs, which was accompanied by a significant decrease in cytoplasmic F-actin content. PAI-1 gene knockdown also decreased cytoplasmic F-actin. PAI-1 inhibition significantly increased the activity of cofilin, an F-actin depolymerase, in WT murine SMCs, but not in PAI-1-deficient SMCs. RNA-sequencing analysis suggested that PAI-039 upregulates AMPK (AMP-activated protein kinase) signaling in SMCs, which was confirmed by Western blotting. Inhibition of AMPK prevented activation of cofilin by PAI-039. In mice, PAI-039 significantly decreased aortic stiffness and tunica media F-actin content without altering the elastin or collagen content. PAI-039 decreases intrinsic SMC stiffness and cytoplasmic stress fiber content. These effects are mediated by AMPK-dependent activation of cofilin. PAI-039 also decreases aortic stiffness in vivo. These findings suggest that PAI-1 is an important regulator of the SMC cytoskeleton and that pharmacological inhibition of PAI-1 has the potential to prevent and treat cardiovascular diseases involving arterial stiffening.

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2024-02-06 | Ligneous conjunctivitis: Fresh-frozen plasma and heparin use intra-and postoperatively, a report of two cases

Ligneous conjunctivitis is a rare chronic form of recurrent membranous inflammation and plasminogen deficiency. Ocular manifestations may be associated with sites other than mucous membranes, such as the oral cavity, internal ear, respiratory, genitals, and kidney. Treatment is extremely difficult because of the lack of topic plasminogen drops, and a high volume is required for systemic supplementation. This report aimed to present two patients with ligneous conjunctivitis treated with membrane excision, topical fresh-frozen plasma, and heparin intra-, and postoperatively. No recurrence was found in the ligneous membrane in the 12-month follow-up. The use of topical fresh-frozen plasma and heparin after membrane excision could be effective to avoid recurrence.

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2021-05-14 | Sex-dependent effects of tranexamic acid on blood-brain barrier permeability and the immune response following traumatic brain injury in mice.

Tranexamic acid (TXA) is an anti-fibrinolytic agent used to reduce bleeding in various conditions including traumatic brain injury (TBI). As the fibrinolytic system also influences the central nervous system and the immune response, TXA may also modulate these parameters following TBI. To determine the effect of TXA on blood-brain barrier (BBB) integrity and changes in immune and motor function in male and female mice subjected to TBI. Wild-type and plasminogen deficient (plg-/-) mice were subjected to TBI then administered either TXA/vehicle. The degree of BBB breakdown, intracerebral hemorrhage (ICH), motor dysfunction, and changes in inflammatory subsets in blood and brain were determined. Tranexamic acid significantly reduced BBB breakdown, and increased blood neutrophils in male mice 3 hours post-TBI. In contrast, TXA treatment of female mice increased BBB permeability and ICH but had no effect on blood neutrophils at the same time-point. TXA improved motor function in male mice but still increased BBB breakdown in female mice 24 hours post-TBI. Brain urokinase-type plasminogen activator (u-PA) antigen and activity levels were significantly higher in injured females compared to males. Because TXA can promote a pro-fibrinolytic effect via u-PA, these sex differences may be related to brain u-PA levels. TXA also increased monocyte subsets and dendritic cells in the injured brain of wild-type male mice 1 week post-TBI. Plg-/- mice of both sexes had reduced BBB damage and were protected from TBI irrespective of treatment indicating that TXA modulation of the BBB is plasmin-dependent. In conclusion, TXA is protective post-TBI but only in male mice.

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gene therapies

2026-02-10 | [Compound heterozygous plasminogen mutations causing hereditary plasminogen deficiency: a family study and mechanistic analysis].

Objective: To investigate the molecular mechanisms underlying compound heterozygous mutations in a patient with hereditary plasminogen (PLG) deficiency. Methods: The proband presented to the First Affiliated Hospital of Wenzhou Medical University with a 2-day history of left-sided limb weakness. Plasminogen activity (PLG∶A) and plasminogen antigen (PLG∶Ag) were measured by chromogenic substrate and enzyme-linked immunosorbent assays, respectively, in the proband and family members (eight individuals across three generations). Sanger sequencing was performed to identify the PLG mutation sites. Bioinformatic analyses were conducted to assess evolutionary conservation and to predict pathogenicity of the mutation sites. Mutant protein models were constructed to examine mutation-induced structural changes. Recombinant plasmid expression vectors were constructed, and in vitro expression of recombinant PLG protein was studied using quantitative real-time PCR (qRT-PCR), ELISA, and Western blot analysis. Results: The proband's PLG∶A was 27% (reference range, 80%-120%) and PLG∶Ag was 103% (reference range, 50%-150%), consistent with type Ⅱ plasminogen deficiency. Genetic analysis revealed compound heterozygous missense mutations in the proband: c.1702G>A (p. Gly568Arg) in exon 14 and c.1858G>A (p. Ala620Thr) in exon 15. The c.1702G>A site is highly conserved across seven species, and is predicted to be pathogenic by bioinformatic tools. Protein modeling showed that p. Gly568Arg introduces a longer side chain and forms a new hydrogen bond with Leu686. In vitro expression showed that neither mutation caused abnormalities in PLG transcript levels, protein expression, or secretion; however, the PLG∶A/PLG∶Ag ratios in the culture supernatants were significantly lower than wild-type for both variants (Ala620Thr: 0.598 ± 0.114 vs 1.000, P=0.013; Gly568Arg: 0.412 ± 0.079 vs 1.000, P=0.022) . Conclusion: The heterozygous missense mutations p.Gly568Arg and p. Ala620Thr are associated with decreased PLG∶A in the family proband and may cause functional impairment by altering protein conformation.

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1997-12-12 | Inhibitory role of plasminogen activator inhibitor-1 in arterial wound healing and neointima formation: a gene targeting and gene transfer study in mice.

Plasminogen-deficient mice display impaired vascular wound healing and reduced arterial neointima formation after arterial injury, suggesting that inhibition of plasmin generation might reduce arterial neointima formation. Therefore, we studied the consequences of plasminogen activator inhibitor-1 (PAI-1) gene inactivation and adenoviral PAI-1 gene transfer on arterial neointima formation. Neointima formation was evaluated in PAI-1-deficient (PAI-1(-/-)) mice with perivascular electric or transluminal mechanical injury. PAI-1 deficiency improved vascular wound healing in both models: the cross-sectional neointimal area was 0.001+/-0.001 mm2 in PAI-1(+/+) and 0.016+/-0.008 mm2 in PAI-1(-/-) mice within 1 week after electric injury (P<.02) and 0.055+/-0.008 mm2 in PAI-1(+/+) and 0.126+/-0.006 mm2 in PAI-1(-/-) mice within 3 weeks after mechanical injury (P<.001). Proliferation of smooth muscle cells was not affected by PAI-1 deficiency. Topographic analysis of arterial wound healing after electric injury revealed that PAI-1(-/-) smooth muscle cells, originating from the uninjured borders, more rapidly migrated into the necrotic center of the arterial wound than wild-type smooth muscle cells. On the basis of immunostaining, PAI-1 expression was markedly upregulated during vascular wound healing. There were no genotypic differences in reendothelialization of the vascular wound. When PAI-1(-/-) mice were intravenously injected with replication-defective adenovirus expressing human PAI-1 (AdCMVPAI-1), plasma PAI-1 antigen levels increased in a dose-dependent fashion up to to 61+/-8 microg/mL with 2x10(9) plaque-forming units (pfu) virus. Luminal stenosis was 35+/-13% in control AdRR5-treated (2x10(9) pfu) and suppressed to 5+/-5% in AdCMVPAI-1-treated (6x10(8) pfu) PAI-1(-/-) mice (P<.002). By affecting cellular migration, PAI-1 plays an inhibitory role in vascular wound healing and arterial neointima formation after injury, and adenoviral PAI-1 gene transfer reduces arterial neointima formation in mice.

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1997-07-08 | Insights in vessel development and vascular disorders using targeted inactivation and transfer of vascular endothelial growth factor, the tissue factor receptor, and the plasminogen system.

VEGF has been proposed to participate in normal and pathological vessel formation. Surprisingly, lack of only a single VEGF allele resulted in embryonic lethality due to abnormal formation of intra- and extra-embryonic vessels. Homozygous VEGF-deficient embryos, generated by tetraploid aggregation, revealed an even more severe defect in vessel formation. These results (1) suggest a tight regulation of early vessel development by VEGF and, indirectly, the presence of other VEGF-like molecules; (2) reveal an unprecedented lethal phenotype associated with heterozygous deficiency of an autosomal gene, and (3) demonstrate that tetraploid aggregation was a valid and the only method to study the phenotype of the homozyogous VEGF-deficient embryos. The dominant and strict dose-dependent role of VEGF in vivo renders this molecule a desirable therapeutic target for promoting or preventing angiogenesis. Tissue factor (TF) is the principal cellular initiator of coagulation and its deregulated expression has been related to thrombogenesis in sepsis, cancer, and inflammation. However, TF appears to be also involved in a variety of non-hemostatic functions including inflammation, cancer, brain function, immune response, and tumor-associated angiogenesis. Surprisingly, TF deficiency resulted in embryonic lethality due to abnormal extra-embryonic vessel development and defective vitelloembryonic circulation. The abnormal yolk sac vasculature is reminiscent of that observed in embryos lacking VEGF, possibly suggesting that both gene functions are interconnected. These targeting studies extend the recently documented role of TF in tumor-associated angiogenesis and warrant further study of its role in angiogenesis during other pathological disorders. The plasminogen system, via its triggers, tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) and its inhibitor, plasminogen activator inhibitor-1 (PAI-1), has been implicated in thrombosis, arterial neointima formation, and atherosclerosis. Studies in mice with targeted gene inactivation of t-PA, u-PA, PAI-1, the urokinase receptor (u-PAR), and plasminogen (Plg) revealed (1) that deficiency of t-PA or u-PA increase the susceptibility to thrombosis associated with inflammation and that combined deficiency of t-PA:u-PA or deficiency of Plg induces severe spontaneous thrombosis; (2) that vascular injury-induced neointima formation is reduced in mice lacking u-PA-mediated plasmin proteolysis, unaltered in t-PA- or u-PAR-deficient mice and accelerated in PAI-1-deficient mice, but that it can be reverted by adenoviral PAI-1 gene transfer; and (3) that atherosclerosis in mice doubly deficient in apolipoprotein E (apoE) and PAI-1 is reduced after 10 weeks of cholesterol-rich diet. Thus, the plasminogen system significantly affects thrombosis, restenosis, and atherosclerosis.

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proteins

2025-11-07 | Human plasma-derived plasminogen replacement in type 1 plasminogen deficiency: a pediatric case with multisystemic manifestation

The article by D€onmez-Demir et al., ‘Novel plasminogen gene mutations in Turkish patients with type I plasminogen deficiency’, recently published in Blood Coagulation and Fibrinolysis[1], was read with great interest. The study’s authors expanded the mutational spectrum of the PLG gene in the Turkish population and emphasized the clinical heterogeneity and the timely recognition of this rare disorder. As highlighted in the discussion, treatment options for type 1 plasminogen deficiency remain limited, and management strategies, including plasminogen replacement therapy, are of particular clinical relevance. In this context, we wish to present our paediatric case demonstrating a multisystemic phenotype and favourable clinical response to human plasma-derived plasminogen replacement.

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2025-09-10 | Advancing Understanding of Ligneous Conjunctivitis: Bridging Pathogenesis, Diagnosis, and Therapy.

This review and case report address ligneous conjunctivitis (LC), a rare ocular condition caused by plasminogen deficiency type 1 (PLGD-1), which manifests as wood-like fibrin-rich membranes on the palpebral conjunctiva. The goal is to provide ophthalmologists-often the first physicians to encounter the condition-with a robust understanding of its systemic manifestations and to highlight current therapeutic strategies, with particular emphasis on the administration of intravenous plasminogen concentrate. We present a clinical LC case alongside a narrative review of published cases, etiology, and treatment approaches. LC initially manifests as erythematous lesions on the palpebral conjunctiva, eventually developing into fibrinous, wood-like membranes. It is typically associated with PLGD-1, a genetic disorder of the plasminogen gene ( PLG ), which results in impaired fibrinolysis and the formation of fibrin deposits. LC often appears within the first year of life, but patients may experience a prolonged period before diagnosis. PLGD-1 is also associated with the development of mucosal lesions in many other organ systems. Contributing factors include chronic inflammation, allergens, infections, and trauma. There have been many proposed treatment approaches for LC, but the recent approval of intravenous plasma-derived human plasminogen concentrate replacement has been an important advance. LC is an ocular disorder with potential vision- and life-threatening complications. The treatment of LC has historically been challenging; however, recognition of its association with PLGD-1 has led to more effective therapies, particularly intravenous plasminogen concentrate. Early diagnosis and coordinated care between ophthalmologists and other specialists, such as hematologists, are crucial to prevent complications, including vision loss.

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2025-07-15 | CO48 | Gynecological involvement in females with congenital plasminogen deficiency type 1

Background and Aims: Congenital plasminogen deficiency type 1 (PLGD1) is an ultrarare disease characterized by the development of fibrin-rich pseudomembranes on mucosal surfaces of several organs and systems, mainly involving the conjunctiva. In affected females, ligneous lesions may occur on the vaginal and cervical surfaces, ovaries, Fallopian tubes and endometrium. Our aim was to conduct a review of the literature on clinical manifestations and therapeutic approaches of genital involvement in females with PLGD1, including our three cases. Methods: A review of the literature was conducted including terms such as ligneous cervicitis, ligneous vaginitis, ligneous endometritis, ligneous conjunctivitis and plasminogen deficiency type 1. Three patients with congenital plasminogen deficiency and genital involvement followed at our center were included in the analysis. Results: Fifty-seven cases of genital ligneous pseudomembranes, consistent with the typical clinical, histological, and laboratory findings of PLGD1, have been described in the literature. These are predominantly case reports and case series, while a number of patients were included in a phase 2-3 clinical study. Nine of these cases were documented before the correlation with plasminogen deficiency was identified. Reported plasminogen activity levels ranged from <2% to 50%. The pseudomembranous lesions have been described in the vagina, cervix, endometrium, ovaries and Fallopian tubes. Including our cases, genital lesions represented the sole clinical manifestation of the disease in 12 of 60 patients (20%), with extragenital involvement, primarily the conjunctiva, observed in the remaining patients. Main symptoms included dysmenorrhea, vaginal discharge, post-coital bleeding, and infertility (15 of 52 reported cases, 28.8%). Histological findings of pseudomembranes require a differential diagnosis with neoplasia, sometimes coexisting with the ligneous lesions. Simple excision of the pseudomembranes was associated with recurrence of the lesions. Data on the specific treatment of the gynecological area were scarce and often empirical: topical and systemic treatments included steroids, cyclosporine, estroprogestins and fresh frozen plasma. The only effective treatment was a replacement therapy with human Glu-plasminogen concentrate, already approved by the FDA. No data were found regarding the quality of life and psychological impact caused by gynecological involvement in patients with PLGD1. Conclusions: In patients with PLGD1, involvement of the genital apparatus is not uncommon, it can represent the sole clinical manifestation of the disease and can lead to infertility. There are very encouraging results from replacement therapy with human plasminogen concentrate, the use of which is still limited worldwide.

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2025-03-16 | How I treat type 1 plasminogen deficiency.

Type 1 plasminogen deficiency (PLGD), an ultrarare disorder caused by PLG pathogenic variants, results in decreased levels of immunoreactive and functional plasminogen. PLGD can cause fibrin-rich pseudomembranes on mucosa that impair tissue/organ function, affect quality of life, and are potentially life threatening. Lesion regression/resolution is facilitated by IV administration of human plasma-derived Glu-plasminogen (IV PLG concentrate), the first and only US Food and Drug Administration-approved specific treatment, licensed in 2021. The diagnosis of PLGD is frequently delayed because of its rarity (1.6 per million) and the variability of the initial medical specialty contact determined by the affected systems. Symptoms are often attributed to more common conditions, such as conjunctivitis, recurrent otitis media, reactive airway disease, etc. This article presents clinical vignettes highlighting strategies for PLGD diagnosis and treatment. Initial evaluation includes a detailed history, laboratory assays, and, at times, radiologic or other procedures. Genetic testing can confirm the diagnosis. Consistent, knowledgeable management is required to promptly identify and treat lesions, even in initially asymptomatic individuals. Personalized treatment may include continuous prophylaxis or intermittent treatment with IV PLG concentrate, dependent on disease severity and clinical course. Specialized facilities such as hemophilia treatment centers offering multidisciplinary care represent medical homes for this ultrarare disorder.

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2024-06-20 | Nonhealing Surgical Wounds in a Patient with Plasminogen Deficiency Type 1 Successfully Treated with Intravenous Plasminogen: A Case Report.

Intravenous plasminogen replacement therapy for patients with plasminogen deficiency type 1 (hypoplasminogenemia) was recently approved for marketing in the US. In this case report, the authors describe a 33-year-old man with hypoplasminogenemia who developed nonhealing postsurgical wounds following trauma to his right hand despite receiving standard treatment for 4 months. The patient was enrolled in a compassionate-use protocol with intravenous plasminogen replacement therapy and experienced prompt resolution of surgical wounds. He was the first human patient to receive replacement therapy with plasminogen, human-tvmh in the US and first to demonstrate cutaneous wound healing in addition to resolution of ligneous lesions attributable to plasminogen deficiency type 1.

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antibodies

2022-06-08 | Deficiency of Urokinase-Type Plasminogen Activator Receptor Is Associated with the Development of Perivascular Fibrosis in Mouse Heart.

It was suggested that the urokinase system plays a certain role in the regulation of activity of the endothelial-mesenchymal transition and in the development of perivascular fibrosis. Urokinase (uPA), the key component of the urokinase system, is a serine protease that binds to its receptor on the cell surface (uPAR) and affects the cell microenvironment components through the formation of plasmin, remodeling of the extracellular matrix, release of growth factors, and initiation of intracellular signals. The heart of PLAUR gene knockout C57BL/129 (uPAR-/-) mice showed signs of vasculopathy: reduced number of capillaries/arterioles, signs of endothelial-mesenchymal transition in endothelial cells, vascular wall remodeling, and deposition of extracellular matrix components. These changes were combined with enhanced expression of urokinase and active forms of TGF-β1. Apparently, uPAR is a part of a multicomponent system that provides multifaceted regulatory effects on the components of forming vessels and vascular wall cells, which allows considering it as a possible target for targeted antifibrotic therapy.

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2016-08-17 | Plasmin Prevents Dystrophic Calcification After Muscle Injury

Extensive or persistent calcium phosphate deposition within soft tissues after severe traumatic injury or major orthopedic surgery can result in pain and loss of joint function. The pathophysiology of soft tissue calcification, including dystrophic calcification and heterotopic ossification (HO), is poorly understood; consequently, current treatments are suboptimal. Here, we show that plasmin protease activity prevents dystrophic calcification within injured skeletal muscle independent of its canonical fibrinolytic function. After muscle injury, dystrophic calcifications either can be resorbed during the process of tissue healing, persist, or become organized into mature bone (HO). Without sufficient plasmin activity, dystrophic calcifications persist after muscle injury and are sufficient to induce HO. Downregulating the primary inhibitor of plasmin (α2-antiplasmin) or treating with pyrophosphate analogues prevents dystrophic calcification and subsequent HO in vivo. Because plasmin also supports bone homeostasis and fracture repair, increasing plasmin activity represents the first pharmacologic strategy to prevent soft tissue calcification without adversely affecting systemic bone physiology or concurrent muscle and bone regeneration. © 2016 American Society for Bone and Mineral Research.

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2004-10-19 | The regulation of liver regeneration by the plasmin/alpha 2-antiplasmin system.

The regeneration after liver injury is regulated by the release and activation of several growth factors. The role of the plasmin/alpha(2)-antiplasmin (alpha(2)-AP) system in liver regeneration was investigated. CCl(4) was injected intraperitoneally into the mice deficient (-/-) in fibrinolytic factors: alpha(2)-AP-/-, plasminogen (Plg) -/-, and Plg-/-.alpha(2)-AP-/-, and wild-type (WT) mice. The liver tissue was examined for its microscopic appearance, fibrinolytic activity, and fibronectin levels. In the gene deficient and WT mice, the livers exhibited the same extent of necrosis 2 days after the CCl(4) injection. The livers of the WT mice normalized after 7 days, and the alpha(2)-AP-/- mice normalized after 5 days. In contrast, the livers of the Plg-/- and Plg-/-.alpha(2)-AP-/- mice remained in the damaged state until 14 days after the liver injury. The injection of anti-alpha(2)-AP antibody in the WT mice improved the regeneration after the liver injury, and the injection of tranexamic acid in the alpha(2)-AP-/- mice reduced. These results suggest that the plasmin/alpha(2)-AP system played an important role in hepatic repair via clearance from the injury area.

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