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The Role of Fibrinolytic System in Health and Disease 2.0
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The Role of Fibrinolytic System in Health and Disease 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 22382

Special Issue Editor

Prof. Dr. Hau C. Kwaan

E-Mail Website
Guest Editor
Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Interests: oncology; leukemia; intracranial hemorrhage; hemostatic dysfunction in acute promyelocytic leukemia; thrombosis; bleeding disorders; fibrinolysis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The proteolytic enzyme plasmin is the central component of the fibrinolytic system (also known as the plasminogen–plasmin system). Originally thought to be a regulator of fibrin removal, it is now known to be more complex. It consists of several serine proteases and their inhibitors (serpins). These are involved in many physiological functions in the pathogenesis of many diseases, including atherosclerosis, obesity, cancer, immune disorders, neuronal degeneration, trauma, inflammation and aging. Knowledge of their role in cancer enables their use as a prognostic factor. Therapeutic use of the various forms of proteases derived from this system has been employed in the form of thrombolytic agents. In addition, small molecules designed to inhibit many of the components of the fibrinolytic system are now available in clinical trials, aimed at the treatment of these various disorders. This remarkable development of our knowledge on fibrinolysis is the present theme of this Special Issue of the International Journal of Molecular Sciences.

Prof. Dr. Hau C. Kwaan
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

  • fibrinolysis
  • plasminogen activators
  • trauma
  • immunity
  • aging

Published Papers (7 papers)

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Research

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20 pages, 3068 KiB  
Article
Anti-Inflammatory and Anti-Fibrotic Effect of Immortalized Mesenchymal-Stem-Cell-Derived Conditioned Medium on Human Lung Myofibroblasts and Epithelial Cells
by Eirini Filidou, Leonidas Kandilogiannakis, Gesthimani Tarapatzi, Michail Spathakis, Paschalis Steiropoulos, Dimitrios Mikroulis, Konstantinos Arvanitidis, Vasilis Paspaliaris and George Kolios
Int. J. Mol. Sci. 2022, 23(9), 4570; https://doi.org/10.3390/ijms23094570 - 20 Apr 2022
Cited by 6 | Viewed by 2542
Abstract
Idiopathic pulmonary fibrosis (IPF) is caused by progressive lung tissue impairment due to extended chronic fibrosis, and it has no known effective treatment. The use of conditioned media (CM) from an immortalized human adipose mesenchymal stem cell line could be a promising therapeutic [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is caused by progressive lung tissue impairment due to extended chronic fibrosis, and it has no known effective treatment. The use of conditioned media (CM) from an immortalized human adipose mesenchymal stem cell line could be a promising therapeutic strategy, as it can reduce both fibrotic and inflammatory responses. We aimed to investigate the anti-inflammatory and anti-fibrotic effect of CM on human pulmonary subepithelial myofibroblasts (hPSM) and on A549 pulmonary epithelial cells, treated with pro-inflammatory or pro-fibrotic mediators. CM inhibited the proinflammatory cytokine-induced mRNA and protein production of various chemokines in both hPSMs and A549 cells. It also downregulated the mRNA expression of IL-1α, but upregulated IL-1β and IL-6 mRNA production in both cell types. CM downregulated the pro-fibrotic-induced mRNA expression of collagen Type III and the migration rate of hPSMs, but upregulated fibronectin mRNA production and the total protein collagen secretion. CM’s direct effect on the chemotaxis and cell recruitment of immune-associated cells, and its indirect effect on fibrosis through the significant decrease in the migration capacity of hPSMs, makes it a plausible candidate for further development towards a therapeutic treatment for IPF. Full article
(This article belongs to the Special Issue The Role of Fibrinolytic System in Health and Disease 2.0)
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14 pages, 3310 KiB  
Article
The Efficacy of Fibrinogen Concentrates in Relation to Cryoprecipitate in Restoring Clot Integrity and Stability against Lysis
by Claire S. Whyte, Akriti Rastogi, Ellis Ferguson, Michela Donnarumma and Nicola J. Mutch
Int. J. Mol. Sci. 2022, 23(6), 2944; https://doi.org/10.3390/ijms23062944 - 09 Mar 2022
Cited by 8 | Viewed by 2815
Abstract
Loss of fibrinogen is a feature of trauma-induced coagulopathy (TIC), and restoring this clotting factor is protective against hemorrhages. We compared the efficacy of cryoprecipitate, and of the fibrinogen concentrates RiaSTAP® and FibCLOT® in restoring the clot integrity in models of [...] Read more.
Loss of fibrinogen is a feature of trauma-induced coagulopathy (TIC), and restoring this clotting factor is protective against hemorrhages. We compared the efficacy of cryoprecipitate, and of the fibrinogen concentrates RiaSTAP® and FibCLOT® in restoring the clot integrity in models of TIC. Cryoprecipitate and FibCLOT® produced clots with higher maximal absorbance and enhanced resistance to lysis relative to RiaSTAP®. The fibrin structure of clots, comprising cryoprecipitate and FibCLOT®, mirrored those of normal plasma, whereas those with RiaSTAP® showed stunted fibers and reduced porosity. The hemodilution of whole blood reduced the maximum clot firmness (MCF) as assessed by thromboelastography. MCF could be restored with the inclusion of 1 mg/mL of fibrinogen, but only FibCLOT® was effective at stabilizing against lysis. The overall clot strength, measured using the Quantra® hemostasis analyzer, was restored with both fibrinogen concentrates but not cryoprecipitate. α2antiplasmin and plasminogen activator inhibitor-1 (PAI-1) were constituents of cryoprecipitate but were negligible in RiaSTAP® and FibCLOT®. Interestingly, cryoprecipitate and FibCLOT® contained significantly higher factor XIII (FXIII) levels, approximately three-fold higher than RiaSTAP®. Our data show that 1 mg/mL fibrinogen, a clinically achievable concentration, can restore adequate clot integrity. However, FibCLOT®, which contained more FXIII, was superior in normalizing the clot structure and in stabilizing hemodiluted clots against mechanical and fibrinolytic degradation. Full article
(This article belongs to the Special Issue The Role of Fibrinolytic System in Health and Disease 2.0)
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Review

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18 pages, 892 KiB  
Review
Renal Fibrosis in Lupus Nephritis
by Savino Sciascia, Martina Cozzi, Alice Barinotti, Massimo Radin, Irene Cecchi, Roberta Fenoglio, Daniele Mancardi, Georgia Wilson Jones, Daniela Rossi and Dario Roccatello
Int. J. Mol. Sci. 2022, 23(22), 14317; https://doi.org/10.3390/ijms232214317 - 18 Nov 2022
Cited by 14 | Viewed by 2418
Abstract
Fibrosis can be defined as a pathological process in which deposition of connective tissue replaces normal parenchyma. The kidney, like any organ or tissue, can be impacted by this maladaptive reaction, resulting in persistent inflammation or long-lasting injury. While glomerular injury has traditionally [...] Read more.
Fibrosis can be defined as a pathological process in which deposition of connective tissue replaces normal parenchyma. The kidney, like any organ or tissue, can be impacted by this maladaptive reaction, resulting in persistent inflammation or long-lasting injury. While glomerular injury has traditionally been regarded as the primary focus for classification and prognosis of lupus nephritis (LN), increasing attention has been placed on interstitial fibrosis and tubular atrophy as markers of injury severity, predictors of therapeutic response, and prognostic factors of renal outcome in recent years. This review will discuss the fibrogenesis in LN and known mechanisms of renal fibrosis. The importance of the chronicity index, which was recently added to the histological categorization of LN, and its role in predicting treatment response and renal prognosis for patients with LN, will be explored. A better understanding of cellular and molecular pathways involved in fibrosis in LN could enable the identification of individuals at higher risk of progression to chronic kidney disease and end-stage renal disease, and the development of new therapeutic strategies for lupus patients. Full article
(This article belongs to the Special Issue The Role of Fibrinolytic System in Health and Disease 2.0)
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21 pages, 2135 KiB  
Review
Molecular Mechanisms and Physiological Changes behind Benign Tracheal and Subglottic Stenosis in Adults
by Alessandro Marchioni, Roberto Tonelli, Alessandro Andreani, Gaia Francesca Cappiello, Matteo Fermi, Fabiana Trentacosti, Ivana Castaniere, Riccardo Fantini, Luca Tabbì, Dario Andrisani, Filippo Gozzi, Giulia Bruzzi, Linda Manicardi, Antonio Moretti, Serena Baroncini, Anna Valeria Samarelli, Massimo Pinelli, Giorgio De Santis, Alessandro Stefani, Daniele Marchioni, Francesco Mattioli and Enrico Cliniadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2022, 23(5), 2421; https://doi.org/10.3390/ijms23052421 - 22 Feb 2022
Cited by 15 | Viewed by 3950
Abstract
Laryngotracheal stenosis (LTS) is a complex and heterogeneous disease whose pathogenesis remains unclear. LTS is considered to be the result of aberrant wound-healing process that leads to fibrotic scarring, originating from different aetiology. Although iatrogenic aetiology is the main cause of subglottic or [...] Read more.
Laryngotracheal stenosis (LTS) is a complex and heterogeneous disease whose pathogenesis remains unclear. LTS is considered to be the result of aberrant wound-healing process that leads to fibrotic scarring, originating from different aetiology. Although iatrogenic aetiology is the main cause of subglottic or tracheal stenosis, also autoimmune and infectious diseases may be involved in causing LTS. Furthermore, fibrotic obstruction in the anatomic region under the glottis can also be diagnosed without apparent aetiology after a comprehensive workup; in this case, the pathological process is called idiopathic subglottic stenosis (iSGS). So far, the laryngotracheal scar resulting from airway injury due to different diseases was considered as inert tissue requiring surgical removal to restore airway patency. However, this assumption has recently been revised by regarding the tracheal scarring process as a fibroinflammatory event due to immunological alteration, similar to other fibrotic diseases. Recent acquisitions suggest that different factors, such as growth factors, cytokines, altered fibroblast function and genetic susceptibility, can all interact in a complex way leading to aberrant and fibrotic wound healing after an insult that acts as a trigger. However, also physiological derangement due to LTS could play a role in promoting dysregulated response to laryngo-tracheal mucosal injury, through biomechanical stress and mechanotransduction activation. The aim of this narrative review is to present the state-of-the-art knowledge regarding molecular mechanisms, as well as mechanical and physio-pathological features behind LTS. Full article
(This article belongs to the Special Issue The Role of Fibrinolytic System in Health and Disease 2.0)
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12 pages, 636 KiB  
Review
Update on Novel Targeted Therapy for Pleural Organization and Fibrosis
by Torry A. Tucker and Steven Idell
Int. J. Mol. Sci. 2022, 23(3), 1587; https://doi.org/10.3390/ijms23031587 - 29 Jan 2022
Cited by 2 | Viewed by 2217
Abstract
Pleural injury and subsequent loculation is characterized by acute injury, sustained inflammation and, when severe, pathologic tissue reorganization. While fibrin deposition is a normal part of the injury response, disordered fibrin turnover can promote pleural loculation and, when unresolved, fibrosis of the affected [...] Read more.
Pleural injury and subsequent loculation is characterized by acute injury, sustained inflammation and, when severe, pathologic tissue reorganization. While fibrin deposition is a normal part of the injury response, disordered fibrin turnover can promote pleural loculation and, when unresolved, fibrosis of the affected area. Within this review, we present a brief discussion of the current IPFT therapies, including scuPA, for the treatment of pathologic fibrin deposition and empyema. We also discuss endogenously expressed PAI-1 and how it may affect the efficacy of IPFT therapies. We further delineate the role of pleural mesothelial cells in the progression of pleural injury and subsequent pleural remodeling resulting from matrix deposition. We also describe how pleural mesothelial cells promote pleural fibrosis as myofibroblasts via mesomesenchymal transition. Finally, we discuss novel therapeutic targets which focus on blocking and/or reversing the myofibroblast differentiation of pleural mesothelial cells for the treatment of pleural fibrosis. Full article
(This article belongs to the Special Issue The Role of Fibrinolytic System in Health and Disease 2.0)
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11 pages, 1083 KiB  
Review
Bleeding Disorders in Primary Fibrinolysis
by Massimo Franchini, Marco Zaffanello and Pier Mannuccio Mannucci
Int. J. Mol. Sci. 2021, 22(13), 7027; https://doi.org/10.3390/ijms22137027 - 29 Jun 2021
Cited by 7 | Viewed by 3533
Abstract
Fibrinolysis is a complex enzymatic process aimed at dissolving blood clots to prevent vascular occlusions. The fibrinolytic system is composed of a number of cofactors that, by regulating fibrin degradation, maintain the hemostatic balance. A dysregulation of fibrinolysis is associated with various pathological [...] Read more.
Fibrinolysis is a complex enzymatic process aimed at dissolving blood clots to prevent vascular occlusions. The fibrinolytic system is composed of a number of cofactors that, by regulating fibrin degradation, maintain the hemostatic balance. A dysregulation of fibrinolysis is associated with various pathological processes that result, depending on the type of abnormality, in prothrombotic or hemorrhagic states. This narrative review is focused on the congenital and acquired disorders of primary fibrinolysis in both adults and children characterized by a hyperfibrinolytic state with a bleeding phenotype. Full article
(This article belongs to the Special Issue The Role of Fibrinolytic System in Health and Disease 2.0)
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14 pages, 2404 KiB  
Review
Annexin A2 in Fibrinolysis, Inflammation and Fibrosis
by Hana I. Lim and Katherine A. Hajjar
Int. J. Mol. Sci. 2021, 22(13), 6836; https://doi.org/10.3390/ijms22136836 - 25 Jun 2021
Cited by 29 | Viewed by 4023
Abstract
As a cell surface tissue plasminogen activator (tPA)-plasminogen receptor, the annexin A2 (A2) complex facilitates plasmin generation on the endothelial cell surface, and is an established regulator of hemostasis. Whereas A2 is overexpressed in hemorrhagic disease such as acute promyelocytic leukemia, its underexpression [...] Read more.
As a cell surface tissue plasminogen activator (tPA)-plasminogen receptor, the annexin A2 (A2) complex facilitates plasmin generation on the endothelial cell surface, and is an established regulator of hemostasis. Whereas A2 is overexpressed in hemorrhagic disease such as acute promyelocytic leukemia, its underexpression or impairment may result in thrombosis, as in antiphospholipid syndrome, venous thromboembolism, or atherosclerosis. Within immune response cells, A2 orchestrates membrane repair, vesicle fusion, and cytoskeletal organization, thus playing a critical role in inflammatory response and tissue injury. Dysregulation of A2 is evident in multiple human disorders, and may contribute to the pathogenesis of various inflammatory disorders. The fibrinolytic system, moreover, is central to wound healing through its ability to remodel the provisional matrix and promote angiogenesis. A2 dysfunction may also promote tissue fibrogenesis and end-organ fibrosis. Full article
(This article belongs to the Special Issue The Role of Fibrinolytic System in Health and Disease 2.0)
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