Biochemical and Biophysical Research Communications
Intratracheal gene transfer of tissue factor pathway inhibitor attenuates pulmonary fibrosis
Section snippets
Materials and methods
Animal treatment. Pulmonary fibrosis was induced in male Wistar rats weighing 280–320 g by a single intratracheal instillation of bleomycin (2 U/kg, Nippon Kayaku, Tokyo, Japan) diluted in sterile endotoxin-free phosphate-buffered saline (PBS), pH 7.4, in a final volume of 300 μl. After anesthesia with pentobarbital sodium (60 mg/kg, intraperitoneal injection), rats received intratracheal instillation of PBS (control), bleomycin or bleomycin + AdTFPI (the recombinant replication-defective adenovirus
Suppression of procoagulant activity and thrombin generation by TFPI overexpression in bleomycin-treated lungs
As previously reported [10], [11], [33], a single intratracheal injection of bleomycin caused remarkable increases in procoagulant activity and thrombin generation in BALF, which began to increase on day 3 and peaked on day 7 (Fig. 1). It is worth noting that while thrombin activity sharply returned to baseline values (Fig. 1C) procoagulant activity remained high on day 14, returning to baseline values on day 21 (Fig. 1B). The explanation for this discrepancy is not clear but it may depend on
Discussion
In the present study, we assessed the pathophysiological implication of TF and the therapeutic value of adenovirus-mediated intratracheal gene transfer of TFPI in bleomycin-associated lung fibrosis [28]. This study showed that TFPI-overexpression almost completely inhibited procoagulant activity and thrombin generation in bleomycin-induced lung injury, thus providing evidence that coagulation activation in this model occurs due to excessive TF expression. The main finding of this study is that
References (39)
- et al.
Increased procoagulant and antifibrinolytic activities in the lungs with idiopathic pulmonary fibrosis
Thromb. Res.
(1995) - et al.
Role of thrombin in pulmonary fibrosis
Lancet
(1995) - et al.
Direct thrombin inhibition reduces lung collagen, accumulation, and connective tissue growth factor mRNA levels in bleomycin-induced pulmonary fibrosis
Am. J. Pathol.
(2001) - et al.
Thrombin is a potent inducer of connective tissue growth factor production via proteolytic activation of protease-activated receptor-1
J. Biol. Chem.
(2000) - et al.
Thrombin differentiates normal lung fibroblasts to a myofibroblast phenotype via the proteolytically activated receptor-1 and a protein kinase C-dependent pathway
J. Biol. Chem.
(2001) - et al.
Absence of proteinase-activated receptor-1 signaling affords protection from bleomycin-induced lung inflammation and fibrosis
Am. J. Pathol.
(2005) - et al.
Factor Xa stimulates fibroblast procollagen production, proliferation, and calcium signaling via PAR1 activation
Exp. Cell Res.
(2005) - et al.
Bovine factor VII. Its purification and complete amino acid sequence
J. Biol. Chem.
(1988) - et al.
Cloning and characterization of a cDNA coding for the lipoprotein-associated coagulation inhibitor shows that it consists of three tandem Kunitz-type inhibitory domains
J. Biol. Chem.
(1988) - et al.
Dilazep, an antiplatelet agent, inhibits tissue factor expression in endothelial cells and monocytes
Blood
(1997)
Synergistic effect of sphingosine 1-phosphate on thrombin-induced tissue factor expression in endothelial cells
Blood
Factor VIIa and thrombin induce the expression of Cyr61 and connective tissue growth factor, extracellular matrix signaling proteins that could act as possible downstream mediators in factor VIIa × tissue factor-induced signal transduction
J. Biol. Chem.
CC-chemokine receptor 2 required for bleomycin-induced pulmonary fibrosis
Cytokine
Disorders of lung matrix remodeling
J. Clin. Invest.
Coagulation cascade proteases and tissue fibrosis
Biochem. Soc. Trans.
Role of thrombin and its major cellular receptor, protease-activated receptor-1, in pulmonary fibrosis
Biochem. Soc. Trans.
Coagulation, fibrinolysis, and fibrin deposition in acute lung injury
Crit. Care Med.
An immunohistochemical study of architectural remodeling and connective tissue synthesis in pulmonary fibrosis
Am. Rev. Respir. Dis.
Prevention of bleomycin-induced lung fibrosis by aerosolization of heparin or urokinase in rabbits
Am. J. Respir. Crit. Care Med.
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Gene therapy strategies for idiopathic pulmonary fibrosis: recent advances, current challenges, and future directions
2021, Molecular Therapy Methods and Clinical DevelopmentCitation Excerpt :Although both studies showed promising results, it was not investigated whether rescued cells displayed harmful phenotypes (e.g., malignant transformation). A different approach to treat bleomycin-induced fibrosis was presented by Kijiyama et al.,41 who inhibited activation of the coagulation cascade by augmenting tissue factor pathway inhibitor (TFPI) expression. Overexpressing TFPI suppressed various aspects of fibrosis (e.g., collagen deposition and expression of profibrotic cytokines) and almost completely eradicated procoagulant activity and thrombin generation in rats.
The impaired proteases and anti-proteases balance in Idiopathic Pulmonary Fibrosis
2018, Matrix BiologyCitation Excerpt :Excessive or smouldering pro-coagulant activity in the alveolar space results from the disruption of the balance between the pro- and anti-coagulant factors, and this imbalance may occur as a result of an on-going stimulus to coagulation or a defect of the natural anti-coagulant or fibrinolytic system. Thus, TF pathway activity is increased in the alveolar compartment of IPF patients [97,98] and its inhibition using overexpression of the endogenous inhibitor ‘Tissue factor pathway inhibitor’ (TFPI) limited pulmonary fibrosis in the bleomycin model [99]. Thrombin is also detected within the lung and intra-alveolar spaces in diverse pulmonary fibrotic conditions [100] and its inhibition reduced lung inflammation and fibrosis in a bleomycin model of pulmonary fibrosis [101,102].
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2009, Advances in PharmacologyCitation Excerpt :Other drugs or chemicals known to produce pulmonary fibrosis in humans are also used in the search for potential antifibrotic drugs. For example, Cantor et al. (1984) produced amiodarone-induced fibrosis in hamsters, while Kennedy et al. (1988) used amiodarone to induce injury in perfused rabbit lungs. Further, Leeder, Brien, and Massey (1994) demonstrated a reduction of amiodarone-induced pulmonary toxicity by N-acetyl cysteine (NAC), and antioxidants reduce silica -induced pulmonary fibrosis in mice (Lombard-Gillooly & Hubbard, 1993).
The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?
2008, International Journal of Biochemistry and Cell BiologyExperimental models for the study of pulmonary fibrosis: Current usefulness and future promise
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