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Protective effect of PN-1 from BM cells in bleomycin-injured chimeric mice. PN-1 2/2 mice and their PN-1 1/1 littermates were irradiated and underwent transplantation with BM from appropriated mice and allowed to recover for 5 weeks before bleomycin-induced lung injury. PN-1 1/1 BM → PN-1 1/1 : PN-1 1/1 mice receiving PN-1 1/1 BM transplants (n 5 10). PN-1 2/2 BM → PN-1 1/1 : PN-1 1/1 mice receiving PN-1 2/2 BM transplants (n 5 8). PN-1 1/1 BM → PN-1 2/2 : PN-1 2/2 mice receiving PN-1 1/1 BM transplants (n 5 7). PN-1 2/2 BM → PN-1 2/2 : PN-1 2/2 mice receiving PN-1 2/2 BM transplants (n 5 5). (A) Percentages of surviving mice undergoing transplantation were plotted over a 14-day period after bleomycin treatment. Log-rank test was used to compare the difference between similar recipient mice. P 5 .03 for PN-1 1/1 BM → PN-1 2/2 vs PN-1 2/2 BM → PN-1 2/2 , and P 5 .002 for PN-1 1/1 BM → PN-1 1/1 vs PN-1 2/2 BM → PN-1 1/1. (B) Masson's trichrome and Sirius red stainings of lung withdrawn the day of euthanasia from PN-1 1/1 and PN-1 2/2 chimeric mice. Representative images are shown. Scale bars, 100 mm.
Source publication
Coagulation and fibrinolytic system deregulation has been implicated in the development of idiopathic pulmonary fibrosis, a devastating form of interstitial lung disease. We used intratracheal instillation of bleomycin to induce pulmonary fibrosis in mice and analyzed the role of serine protease inhibitor E2 (serpinE2)/protease nexin-1 (PN-1), a ti...
Citations
... A study by François found that imatinib inhibits the activation of thrombin to attenuate lung injury. This nding suggests that imatinib may attenuate the damaging effects of disturbances in the coagulation system on lung tissue by inhibiting the activation of thrombi [24] , which is consistent with our analysis of the sequencing results. Additionally, as mentioned earlier, mitochondrial damage and disruption of the oxidative respiratory chain are also key changes in the development of sepsis. ...
Background
Acute lung injury (ALI) is the most common complication of sepsis. Despite considerable progress in the treatment of sepsis, morbidity and mortality associated with sepsis-induced ALI remain high and effective treatment strategies are lacking. A previous study has shown that imatinib reduces the rate of acute pulmonary damage in septic mice, and this particular study was ongoing for more than a decade. However, the molecular mechanism by which imatinib reduces lung injury in septic mice remains unclear. Therefore, the current study aimed to investigate the potential mechanism by which imatinib alleviates ALI in septic mice.
Methods
A septicemia model was established by intraperitoneal injection of lipopolysaccharide (LPS), followed by tail vein injection of imatinib in the treatment group and normal saline injection in the control group. Flow cytometry was used to detect inflammatory factors, and hematoxylin staining was used to detect pathological injury to the lung tissue. TMT quantitative labeling technology was used for proteomic sequencing analysis. The main target protein was identified through bioinformatics and its expression was confirmed using western blotting.
Results
We identified 706 differentially expressed proteins, 128 of which were associated with the protective effects of imatinib against septic lung injury. Functional enrichment analysis indicated that imatinib-related differentially expressed proteins may be related to electron transfer, coagulation, and endothelial cell regulation in the oxidative respiratory chain. Enrichment of the nuclear factor-kappa B (NF-kB) signaling pathway, complement-coagulation cascade, chemokine signaling pathway, and cytochrome-cytochrome receptor interaction pathway were also observed. Additionally, we found that the expression of CCAAT/enhancer-binding protein delta (CEBPD) and pyruvate dehydrogenase kinase 4 (PDK4) increased in the sepsis group, but decreased in the imatinib group, consistent with our sequencing results.
Conclusion
Imatinib may reduce ALI in mice with sepsis by participating in oxidative respiratory and inflammatory responses, clotting response-related signaling pathways, and downregulating CEBPD and PDK4 expression.
... 5 SERPINE2deficient mice exhibit important antithrombotic and antifibrinolytic properties. 6 Aberrant SERPINE2 expression also influences tumorigenesis of various cancers and contributes to tumor invasion and metastasis. 7e13 Furthermore, it promotes cell migration, invasion, and proliferation in esophageal squamous cell carcinoma. ...
Background/purpose
The serpin peptidase inhibitor, clade E, member 2 (SERPINE2), is upregulated in breast cancer, prostate cancer, and urothelial carcinoma; however, limited information exists regarding its expression in oral cancer. Therefore, this study aimed to analyze the association between SERPINE2 expression and oral squamous cell carcinoma (OSCC) outcomes.
Materials and methods
SERPINE2 mRNA and protein expression in patients with head and neck squamous cell carcinoma and OSCC were investigated using online databases and tissue-array analysis. Its relationship with clinicopathological characteristics, OSCC prognosis and its biological function in OSCC cells were explored.
Results
Analysis using online databases revealed higher SERPINE2 expression in tumor tissues and its role as a prognostic factor. High SERPINE2 protein levels were significantly correlated with adverse pathological parameters, including advanced clinical stage and tumor status (P < 0.001), lymph nodes (P = 0.014), and distant metastases (P = 0.013). High SERPINE2 expression was associated with worse overall survival (P < 0.001) and was identified as an independent prognostic factor for OSCC. In vitro studies revealed that SERPINE2 knockdown significantly reduced cell proliferation, migration, and invasion in OSCC cell lines.
Conclusion
This study suggests that SERPINE2 may serve as a prognostic biomarker and potential therapeutic target for oral cancer.
... These findings suggest that the platelet is an important source of PN1 and confers anticoagulant activity through the ability to inhibit thrombin (185). Consistent with the clinically observed lung phenotype, PN1 deficient mice have reduced survival in a bleomycin induced lung injury model (186). Loss of PN1 led to increased inflammation and activation of coagulation in the lung (186). ...
... Consistent with the clinically observed lung phenotype, PN1 deficient mice have reduced survival in a bleomycin induced lung injury model (186). Loss of PN1 led to increased inflammation and activation of coagulation in the lung (186). Bone marrow chimeras demonstrated that this phenotype was driven by loss of PN1 in hematopoietic cells and could be reversed by inhibition of thrombin or PAR4 activation (186). ...
... Loss of PN1 led to increased inflammation and activation of coagulation in the lung (186). Bone marrow chimeras demonstrated that this phenotype was driven by loss of PN1 in hematopoietic cells and could be reversed by inhibition of thrombin or PAR4 activation (186). ...
Appropriate activation of coagulation requires a balance between procoagulant and anticoagulant proteins in blood. Loss in this balance leads to hemorrhage and thrombosis. A number of endogenous anticoagulant proteins, such as antithrombin and heparin cofactor II, are members of the serine protease inhibitor (SERPIN) family. These SERPIN anticoagulants function by forming irreversible inhibitory complexes with target coagulation proteases. Mutations in SERPIN family members, such as antithrombin, can cause hereditary thrombophilias. In addition, low plasma levels of SERPINs have been associated with an increased risk of thrombosis. Here, we review the biological activities of the different anticoagulant SERPINs. We further consider the clinical consequences of SERPIN deficiencies and insights gained from preclinical disease models. Finally, we discuss the potential utility of engineered SERPINs as novel therapies for the treatment of thrombotic pathologies.
... Our results show that PN-1 deficiency favours inflammatory www.nature.com/scientificreports/ cell recruitment during hindlimb ischemia similarly to what was shown during lung inflammation 36 . Thus, PN-1-deficiency allowed enhanced perfusion not only via increased endothelial cell proliferation but also via enhanced leukocyte recruitment that is known to be strongly involved in collateralization 37,38 . ...
We previously identified the inhibitory serpin protease nexin-1 (PN-1) as an important player of the angiogenic balance with anti-angiogenic activity in physiological conditions. In the present study, we aimed to determine the role of PN-1 on pathological angiogenesis and particularly in response to ischemia, in the mouse model induced by femoral artery ligation. In wild-type (WT) muscle, we observed an upregulation of PN-1 mRNA and protein after ischemia. Angiography analysis showed that femoral artery perfusion was more rapidly restored in PN-1−/− mice than in WT mice. Moreover, immunohistochemistry showed that capillary density increased following ischemia to a greater extent in PN-1−/− than in WT muscles. Moreover, leukocyte recruitment and IL-6 and MCP-1 levels were also increased in PN-1−/− mice compared to WT after ischemia. This increase was accompanied by a higher overexpression of the growth factor midkine, known to promote leukocyte trafficking and to modulate expression of proinflammatory cytokines. Our results thus suggest that the higher expression of midkine observed in PN-1- deficient mice can increase leukocyte recruitment in response to higher levels of MCP-1, finally driving neoangiogenesis. Thus, PN-1 can limit neovascularisation in pathological conditions, including post-ischemic reperfusion of the lower limbs.
... PN-1 appears to be importantly involved in fibrotic processes. Interestingly, depending on the affected tissue, PN-1 displays either anti-fibrotic properties as described in pulmonary fibrosis (47) or in contrast, pro-fibrotic properties as described here in cardiac fibrosis or as reported in scleroderma, a disease also characterized by ECM accumulation in skin and visceral tissue (48). The link between PN-1 and cardiac fibrosis can also be mediated, at least in part, by its antiprotease inhibitor activity, in particular by its ability to inhibit thrombin and uPA. ...
The balance between proteases and protease inhibitors plays a critical role in tissue remodeling during cardiovascular diseases. Different serine protease inhibitors termed serpins, which are expressed in the cardiovascular system, can exert a fine-tuned regulation of protease activities. Among them, protease nexin-1 (PN-1, encoded by SERPINE2 ) is a very powerful thrombin inhibitor and can also inactivate plasminogen activators and plasmin. Studies have shown that this serpin is expressed by all cell subpopulations in the vascular wall and by circulating cells but is barely detectable in plasma in the free form. PN-1 present in platelet granules and released upon activation has been shown to present strong antithrombotic and antifibrinolytic properties. PN-1 has a broad spectrum of action related to both hemostatic and blood vessel wall protease activities. Different studies showed that PN-1 is not only an important protector of vascular cells against protease activities but also a significant actor in the clearance of the complexes it forms with its targets. In this context, PN-1 overexpression has been observed in the pathophysiology of thoracic aortic aneurysms (TAA) and during the development of atherosclerosis in humans. Similarly, in the heart, PN-1 has been shown to be overexpressed in a mouse model of heart failure and to be involved in cardiac fibrosis. Overall, PN-1 appears to serve as a “hand brake” for protease activities during cardiovascular remodeling. This review will thus highlight the role of PN-1 in the cardiovascular system and deliver a comprehensive assessment of its position among serpins.
Serine protease inhibitors (serpins) are the most numerous and widespread multifunctional protease inhibitor superfamily and are expressed by all eukaryotes. Serpin E2 (serpin peptidase inhibitor, clade E, member 2), a member of the serine protease inhibitor superfamily is a potent endogenous thrombin inhibitor, mainly found in the extracellular matrix and platelets, and expressed in numerous organs and secreted by many cell types. The multiple functions of serpin E2 are mainly mediated through regulating urokinase-type plasminogen activator (uPA, also known as PLAU), tissue-type plasminogen activator (tPA, also known as PLAT), and matrix metalloproteinase activity, and include hemostasis, cell adhesion, and promotion of tumor metastasis. The importance serpin E2 is clear from its involvement in numerous physiological and pathological processes. In this review, we summarize the structural characteristics of the Serpin E2 gene and protein, as well as its roles physiology and disease.
Our previous study found that miR‐26a alleviates aldosterone‐induced tubulointerstitial fibrosis (TIF). However, the effect of miR‐26a on TIF in diabetic kidney disease (DKD) remains unclear. This study clarifies the role and possible mechanism of exogenous miR‐26a in controlling the progression of TIF in DKD models. Firstly, we showed that miR‐26a was markedly decreased in type 2 diabetic db/db mice and mouse tubular epithelial cells (mTECs) treated with high glucose (HG, 30 mM) using RT‐qPCR. We then used adeno‐associated virus carrying miR‐26a and adenovirus miR‐26a to enhance the expression of miR‐26a in vivo and in vitro. Overexpressing miR‐26a alleviated the TIF in db/db mice and the extracellular matrix (ECM) deposition in HG‐stimulated mTECs. These protective effects were caused by reducing expression of protease‐activated receptor 4 (PAR4), which involved in multiple pro‐fibrotic pathways. The rescue of PAR4 expression reversed the anti‐fibrosis activity of miR‐26a. We conclude that miR‐26a alleviates TIF in DKD models by directly targeting PAR4, which may provide a novel molecular strategy for DKD therapy.
