Thrombin and Thrombin Peptides in Wound Healing and Tissue Repair

Olszewska-Pazdrak, Barbara; Bergmann, John S.; Fuller, Gerald M.; Carney, Darrell H.

doi:10.1007/978-0-387-09637-7_7

Cited by 3 publications

(4 citation statements)

References 60 publications

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“…These results are consistent with the hypothesis that TP508 represents a natural breakdown product of thrombin that is released from fibrin clots into circulation to stimulate tissue revascularization and repair [43, 44]. Studies are currently underway in our laboratory to identify the molecular mechanisms by which TP508 potentiates VEGF-stimulated intracellular signaling and endothelial cell functions in HCAE cells.…”

Section: Discussionsupporting

confidence: 86%

Systemic Administration of Thrombin Peptide TP508 Enhances VEGF-Stimulated Angiogenesis and Attenuates Effects of Chronic Hypoxia

Olszewska-Pazdrak

Carney²

2013

J Vasc Res

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Revascularization of chronic wounds and ischemic tissue is attenuated by endothelial dysfunction and the inability of angiogenic factors to stimulate angiogenesis. We recently showed that TP508, a nonproteolytic thrombin peptide, increases perfusion and NO-dependent vasodilation in hearts with chronic ischemia and stimulates NO production by endothelial cells. In this study, we investigated systemic in vivo effects of TP508 on VEGF-stimulated angiogenesis in vitro using aortic explants in normoxic and hypoxic conditions. Mice were injected with saline or TP508 and 24 h later aortas were removed and cultured to quantify endothelial sprouting. TP508 injection increased endothelial sprouting and potentiated the in vitro response to VEGF. Exposure of control explants to hypoxia inhibited basal and VEGF-stimulated endothelial cell sprouting. This effect of hypoxia was significantly prevented by TP508 injection. Thus, TP508 systemic administration increases responsiveness of aortic endothelial cells to VEGF and diminishes the effect of chronic hypoxia on endothelial cell sprouting. Studies using human endothelial cells in culture suggest that protective effects of TP508 during hypoxia may involve stimulation of endothelial cell NO production. These data suggest potential clinical benefit of using a combination of systemic TP508 and local VEGF as a therapy for revascularization of ischemic tissue.

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Section: Discussionsupporting

confidence: 86%

Systemic Administration of Thrombin Peptide TP508 Enhances VEGF-Stimulated Angiogenesis and Attenuates Effects of Chronic Hypoxia

Olszewska-Pazdrak

Carney²

2013

J Vasc Res

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“…Moreover, thrombin elicits numerous cellular responses, including increased CAM expression and growth factor and cytokine release by endothelial cells, as well as growth stimulation of both smooth muscle and fibroblast cells ( 25 ). Hence, thrombin´s roles expand to physiological situations involving not only hemostasis, but also immunomodulation and tissue regeneration ( 26 ). In this perspective, it is interesting to note that TCPs in the size range of 2–11 kDa indeed are present in human wound fluids as well as fibrin sloughs from acute as well as infected wounds ( 9 , 11 , 27 ).…”

Section: Discussionmentioning

confidence: 99%

“…Based on these findings, the formation of such immunomodulatory antimicrobial TCPs suggests that thrombin autolysis and proteolysis jointly modulate thrombin function from coagulation toward host defense and immunomodulation. This is of importance considering the elevated levels of thrombin produced during coagulation and the vital role of thrombin in wound healing ( 26 ). On the contrary, overactivation of thrombin autolysis yielding γ-thrombin with impaired fibrinogen activity and platelet aggregation may impair hemostasis and wound healing.…”

Section: Discussionmentioning

confidence: 99%

Cell-Free DNA Promotes Thrombin Autolysis and Generation of Thrombin-Derived C-Terminal Fragments

et al. 2021

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Cell-free DNA (cfDNA) is the major structural component of neutrophil extracellular traps (NETs), an innate immune response to infection. Antimicrobial proteins and peptides bound to cfDNA play a critical role in the bactericidal property of NETs. Recent studies have shown that NETs have procoagulant activity, wherein cfDNA triggers thrombin generation through activation of the intrinsic pathway of coagulation. We have recently shown that thrombin binds to NETs in vitro and consequently can alter the proteome of NETs. However, the effect of NETs on thrombin is still unknown. In this study, we report that DNA binding leads to thrombin autolysis and generation of multiple thrombin-derived C-terminal peptides (TCPs) in vitro. Employing a 25-residue prototypic TCP, GKY25 (GKYGFYTHVFRLKKWIQKVIDQFGE), we show that TCPs bind NETs, thus conferring mutual protection against nuclease and protease degradation. Together, our results demonstrate the complex interplay between coagulation, NET formation, and thrombin cleavage and identify a previously undisclosed mechanism for formation of TCPs.

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“…In addition to hemostasis, thrombin also has roles in tissue repair (30), development (31), and in inflammation (32). Many of the effects of thrombin on platelets and endothelial cells are elicited through interaction with a family of transmembrane G-protein-coupled receptors, termed protease-activated receptors (PARs) (33).…”

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confidence: 99%

Thrombin Cleavage of Inter-α-inhibitor Heavy Chain 1 Regulates Leukocyte Binding to an Inflammatory Hyaluronan Matrix

Petrey

Motte

2016

Journal of Biological Chemistry

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Edited by Amanda FosangDynamic alterations of the extracellular matrix in response to injury directly modulate inflammation and consequently the promotion and resolution of disease. During inflammation, hyaluronan (HA) is increased at sites of inflammation where it may be covalently modified with the heavy chains (HC) of inter-␣-trypsin inhibitor. Deposition of this unique, pathological form of HA (HC-HA) leads to the formation of cable-like structures that promote adhesion of leukocytes. Naive mononuclear leukocytes bind specifically to inflammation-associated HA matrices but do not adhere to HA constitutively expressed under homeostatic conditions. In this study, we have directly investigated a role for the blood-coagulation protease thrombin in regulating the adhesion of monocytic cells to smooth muscle cells producing an inflammatory matrix. Our data demonstrate that the proteolytic activity of thrombin negatively regulates the adhesion of monocytes to an inflammatory HC-HA complex. This effect is independent of protease-activated receptor activation but requires proteolytic activity toward a novel substrate. Components of HC-HA complexes were predicted to contain conserved thrombin-susceptible cleavage sites based on sequence analysis, and heavy chain 1 (HC1) was confirmed to be a substrate of thrombin. Thrombin treatment is sufficient to cleave HC1 associated with either cell-surface HA or serum inter-␣-trypsin inhibitor. Furthermore, thrombin treatment of the inflammatory matrix leads to dissolution of HC-HA cable structures and abolishes leukocyte adhesion. These data establish a novel mechanism whereby thrombin cleavage of HC1 regulates the adhesive properties of an inflammatory HA matrix.

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Thrombin and Thrombin Peptides in Wound Healing and Tissue Repair

Cited by 3 publications

References 60 publications

Systemic Administration of Thrombin Peptide TP508 Enhances VEGF-Stimulated Angiogenesis and Attenuates Effects of Chronic Hypoxia

Systemic Administration of Thrombin Peptide TP508 Enhances VEGF-Stimulated Angiogenesis and Attenuates Effects of Chronic Hypoxia

Cell-Free DNA Promotes Thrombin Autolysis and Generation of Thrombin-Derived C-Terminal Fragments

Thrombin Cleavage of Inter-α-inhibitor Heavy Chain 1 Regulates Leukocyte Binding to an Inflammatory Hyaluronan Matrix

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