Elevation of plasma free PAI-1 levels as an integrated endothelial response to severe burns

Aoki, Katsunori; Aikawa, Naoki; Sekine, Keitaro; Yamazaki, Megumi; Mimura, Takuya; Urano, Tetsumei; Takada, Akikazu

doi:10.1016/s0305-4179(01)00011-0

Cited by 35 publications

(51 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Heterotopic ossification often occurs following musculoskeletal trauma associated with electrocution, burn/blast injuries, or with neurological injury (49)(50)(51)(52). Although these conditions have been anecdotally associated with diminished fibrinolytic activity (53)(54)(55), there are no reports that suggest that plasmin(ogen) is directly involved in preventing heterotopic ossification. It has been determined that absence of uPA results in spontaneous heterotopic ossification in mice with Duschenne's muscular dystrophy, although it was not determined whether this was secondary to a deficiency of Figure 7.…”

Section: Murine Femur Fracture Modelmentioning

confidence: 99%

Fibrinolysis is essential for fracture repair and prevention of heterotopic ossification

Yuasa¹,

Mignemi²,

Nyman³

et al. 2015

J. Clin. Invest.

View full text Add to dashboard Cite

Section: Murine Femur Fracture Modelmentioning

confidence: 99%

Fibrinolysis is essential for fracture repair and prevention of heterotopic ossification

Yuasa¹,

Mignemi²,

Nyman³

et al. 2015

J. Clin. Invest.

View full text Add to dashboard Cite

“…TGF-␤1 released from platelets during trauma or surgery might also contribute to the transient increases in plasma levels of PAI-1 that occur after these phenomena if the released latent TGF-␤1 becomes activated intravascularly and systemically activates endothelial cells. [41][42][43][44][45][46][47] This would provide a valuable homeostatic link between platelet activation to arrest hemorrhage and transient inhibition of fibrinolysis to allow the early unopposed deposition of fibrin to secure hemostasis. In addition, the ability of shear force to activate latent TGF-␤1 makes TGF-␤1 a potential shear sensor in addition to being a cellular effector.…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo evidence for shear-induced activation of latent transforming growth factor-β1

Ahamed

Burg

Yoshinaga

et al. 2008

Blood

136

163

View full text Add to dashboard Cite

Transforming growth factor-␤1 (TGF-␤1) has potent physiologic and pathologic effects on a variety of cell types at subnanomolar concentrations. Platelets contain 40 times as much TGF-␤1 as other cells and secrete it as an inactive (latent) form in complex with latency-associated peptide (LAP), which is disulfide bonded via Cys33 to latent TGF-␤ binding protein 1 (LTBP-1). Little is known about how latent TGF-␤1 becomes activated in vivo.Here we show that TGF-␤1 released from platelets or fibroblasts undergoes dramatic activation when subjected to stirring or shear forces, providing a potential mechanism for physiologic control. Thioldisulfide exchange appears to contribute to the process based on the effects of thiol-reactive reagents and differences in thiol labeling of TGF-␤1 before and after stirring or shear. Activation required the presence of LTBP, as TGF-␤1 contained in complex with only LAP could not be activated by stirring when studied as either a recombinant purified protein complex or in the platelet releasates or sera of mice engineered to contain an LAP C33S mutation. Release IntroductionTransforming growth factor-␤1 (TGF-␤1) has potent physiologic and pathologic effects on a variety of cell types at subnanomolar concentrations, including cells of the immune and hematopoietic systems, as well as malignant cells and fibroblasts, 1 with the latter responding with increased collagen production leading to tissue fibrosis. 2 Nearly all cellular TGF-␤1 exists, however, in a biologically inactive (latent) form in a noncovalent complex with the remaining portion of its precursor molecule, latency-associated peptide (LAP), which is disulfide bonded to a latent TGF-␤ binding protein 3,or 4), forming the large latent complex (LLC). 3 Although much is known about the signaling mechanisms and downstream effects of TGF-␤1, 4 and several latent TGF-␤1 activating mechanisms have been identified in vitro (reviewed in Annes et al 3 ), little is known about the physiologic mechanisms that control latent TGF-␤1 activation in vivo. Recent data support activation of LLC TGF-␤1 via a traction mechanism, 3,[5][6][7][8][9][10][11] with LAP binding to integrins ␣V␤5, ␣V␤6, and ␣V␤8, and LTBP-1 binding to extracellular matrix.Blood platelets are a rich source of TGF-␤1, containing 40 to 100 times as much as other cells, 12 and releasing it when activated by a variety of agents, including thrombin, which is produced during blood clotting. [13][14][15][16][17][18][19] Virtually all of the TGF-␤1 released from platelets is in the LLC. 3,16 Because platelet latent TGF-␤1 is released into the circulation, and because traction on the molecule has been proposed as a mechanism of latent TGF-␤1 activation, 5,6 we hypothesized that intravascular shear force may serve as an analog of traction mediated by cellular contraction and contribute to the activation of latent TGF-␤1 released from platelets. We therefore tested this hypothesis by both in vitro and in vivo experiments. Methods Antibodies and reagentsAnti-TGF-␤1 (polyclonal chi...

show abstract

“…This physiologically important molecule is deficient in pathological conditions such as thermal injury [7][8][9]. The resulting hypercoagulable state in burn patients leads to the impaired tissue perfusion, which may result in multiple organ derangements, including pulmonary dysfunction and delayed wound healing.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that the hypercoagulable state in burn patients during the initial 24 h was associated with high levels of activated Factor VII, thrombin/antithrombin complex, PAI-1 (plasminogen activator inhibitor-1), and low levels of antithrombin and protein C [7]. In addition, a number of investigators have documented that plasma concentrations of antithrombin are markedly reduced in burn patients [8,9]. Recently, Niedermayr and coworkers [10] reported that antithrombin deficiency in burn patients correlates strongly with total burned surface area, the presence of inhalation injury, a longer hospital stay and increased mortality.…”

Section: Introductionmentioning

confidence: 99%

Combined anticoagulants ameliorate acute lung injury in sheep after burn and smoke inhalation

et al. 2008

View full text Add to dashboard Cite

Burn and smoke inhalation-related multiple organ dysfunction is associated with a severe fall in the plasma concentration of antithrombin. Therefore the aim of the present study was to test the hypothesis that intravenous administration of recombinant human antithrombin in combination with aerosolized heparin will ameliorate acute lung injury in sheep exposed to cutaneous burn and smoke inhalation. Sheep were prepared operatively for study and, 7 days post-surgery, sheep were given a cutaneous burn (40% of total body surface area, third-degree burn) and insufflated with cotton smoke (48 breaths, <40 degrees C) under halothane anaesthesia. After injury, sheep were placed on a ventilator and resuscitated with Ringer's lactate solution. The animals were divided into three groups: sham group (non-injured and non-treated; n=6), saline group (injured and received saline; n=6) and rhAT.iv.+Hep group [injured and treated with rhAT (recombinant human antithrombin) and heparin; n=6]. In the rhAT.iv.+Hep group, rhAT was infused continuously for 48 h starting 1 h post-injury with a dose of 0.34 mg.h(-1).kg(-1) of body weight and heparin (10000 units) was aerosolized every 4 h starting at 1 h post-injury. The experiment lasted 48 h. Haemodynamics were stable in sham group, whereas the saline-treated sheep developed multiple signs of acute lung injury, including decreased pulmonary gas exchange, increased inspiratory pressures, extensive airway obstruction and increased pulmonary oedema. These pathological changes were associated with a severe fall in plasma antithrombin concentration, lung tissue accumulation of leucocytes and excessive production of NO. Treatment of injured sheep with anticoagulants attenuated all of the pulmonary pathophysiology observed. In conclusion, the results provide definitive evidence that anticoagulant therapy may be a novel and effective treatment tool in the management of burn patients with concomitant smoke inhalation injury.

show abstract

Elevation of plasma free PAI-1 levels as an integrated endothelial response to severe burns

Cited by 35 publications

References 13 publications

Fibrinolysis is essential for fracture repair and prevention of heterotopic ossification

Fibrinolysis is essential for fracture repair and prevention of heterotopic ossification

In vitro and in vivo evidence for shear-induced activation of latent transforming growth factor-β1

Combined anticoagulants ameliorate acute lung injury in sheep after burn and smoke inhalation

Contact Info

Product

Resources

About