Dataset Information

Lee2010_ThrombinActivation_OneForm

ABSTRACT: Chang Jun Lee, Sangwook Wu, Changsun Eun & Lee G. Pedersen. A revisit to the one form kinetic model of prothrombinase. Biophysical Chemistry 149, 1-2 (2010). Thrombin is generated enzymatically from prothrombin by two pathways with the intermediates of meizothrombin and prethrombin-2. Experimental concentration profiles from two independent groups for these two pathways have been re-analyzed. By rationally combining the independent data sets, a simple mechanism can be established and rate constants determined. A structural model is consistent with the data-derived finding that mechanisms that feature channeling or ratcheting are not necessary to describe thrombin production.

SUBMITTER: Michael Schubert

PROVIDER: BIOMD0000000364 | BioModels | 2024-09-02

REPOSITORIES: BioModels

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			Action	DRS
	BIOMD0000000364?filename=BIOMD0000000364-biopax2.owl	Owl
	BIOMD0000000364?filename=BIOMD0000000364-biopax3.owl	Owl
	BIOMD0000000364?filename=BIOMD0000000364-matlab.m	Other
	BIOMD0000000364?filename=BIOMD0000000364.m	Other
	BIOMD0000000364?filename=BIOMD0000000364.ode	Other

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A revisit to the one form kinetic model of prothrombinase.

Lee Chang Jun CJ Wu Sangwook S Eun Changsun C Pedersen Lee G LG

Biophysical chemistry 20100325 1-2

Thrombin is generated enzymatically from prothrombin by two pathways with the intermediates of meizothrombin and prethrombin-2. Experimental concentration profiles from two independent groups for these two pathways have been re-analyzed. By rationally combining the independent data sets, a simple mechanism can be established and rate constants determined. A structural model is consistent with the data-derived finding that mechanisms that feature channeling or ratcheting are not necessary to desc ...[more]

PMID: 20435402

Publication: 1/2

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Project description:The lymphatic vasculature regulates lung homeostasis through drainage of fluid and trafficking of immune cells and plays a key role in the response to lung injury in several disease states. We have previously shown that lymphatic dysfunction occurs early in the pathogenesis of chronic obstructive pulmonary disease (COPD) caused by cigarette smoke (CS) and that this is associated with increased thrombin and fibrin clots in lung lymph. However, the direct effects of CS and thrombin on lymphatic endothelial cells (LECs) in COPD are not entirely clear. Studies of the blood vasculature have shown that COPD is associated with increased thrombin, which causes endothelial dysfunction after CS exposure and is characterized by changes in the expression of coagulation factors and leukocyte adhesion proteins. Here, we determined whether similar changes occur in LECs. We used an in vitro cell culture system and treated human lung microvascular lymphatic endothelial cells with cigarette smoke extract (CSE) and/or thrombin. We found that CSE treatment led to decreased fibrinolytic activity in LECs, which was associated with increased expression of plasminogen activator inhibitor 1 (PAI-1). LECs treated with both CSE and thrombin together had a decreased expression of TFPI and an increased expression of vascular adhesion molecules. RNA sequencing of lung LECs isolated from mice exposed to CS also showed upregulation of prothrombotic and inflammatory pathways at both acute and chronic exposure time points. Analysis of publicly available single-cell RNA sequencing of LECs as well as immunohistochemical staining of lung tissue from COPD patients supported these data and showed an increased expression of inflammatory markers in LECs from COPD patients compared to those from controls. These studies suggest that in parallel with blood vessels, the lymphatic endothelium undergoes inflammatory changes associated with CS exposure and increased thrombin in COPD. Further research is needed to unravel the mechanisms by which these changes affect lymphatic function and drive tissue injury in COPD.