The role of urokinase in idiopathic pulmonary fibrosis and implication for therapy

Gharaee−Kermani, Mehrnaz; Hu, Biao; Phan, Sem H.; Gyetko, Margaret R.

doi:10.1517/13543784.17.6.905

Cited by 18 publications

(10 citation statements)

References 88 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although little is known about the anti-fibrosis function of uPA, some studies revealed that overexpression of uPA is involved in collagen degradation, alleviating liver fibrosis [28], and that uPA can accelerate the invasion of retinal pigment epithelial cells through collagen gels [29]. In terms of idiopathic pulmonary fibrosis, Gharaee-Kermani et al suggested that an approach to target uPA may be a promising new therapeutic strategy [30]. On the other hand, the pro-fibrosis function of uPA was found in cardiac fibrosis, for example, macrophage-derived uPA increases collagen level following myocardial ischemia [31].…”

Section: Discussionmentioning

confidence: 99%

MiR‐10a and miR‐181c regulate collagen type I generation in hypertrophic scars by targeting PAI‐1 and uPA

Zhu

Bai

et al. 2014

FEBS Letters

View full text Add to dashboard Cite

Edited by Tamas DalmayKeywords: MicroRNA Hypertrophic scar Collagen type 1 Urokinase type plasminogen activator Plasminogen activator inhibitor-1 a b s t r a c t Urokinase type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) have been proposed to play key roles in extracellular matrix (ECM) deposition in hypertrophic scars (HS). Here, we found that in HS fibroblasts (HFs) miR-181c and miR-10a were differentiallyexpressed and targeted uPA and PAI-1, respectively. The production of Type 1 collagen (Col1) was inhibited by miR-181c knockdown or miR-10a overexpression in HFs, and this resulted in increased levels of metalloproteinase 1 (MMP1). These results suggest that the miR-181c-uPA and miR-10a-PAI-1 regulatory pathways have an integral role in HS pathogenesis.

show abstract

Section: Discussionmentioning

confidence: 99%

MiR‐10a and miR‐181c regulate collagen type I generation in hypertrophic scars by targeting PAI‐1 and uPA

Zhu

Bai

et al. 2014

FEBS Letters

View full text Add to dashboard Cite

show abstract

“…Indeed, pulmonary disturbances in coagulation and fibrinolysis have been described with remarkable uniformity with the acute respiratory distress syndrome (ARDS) [36-38], pneumonia [36,39], and ventilator-associated lung injury [40]. In addition, pulmonary coagulopathy has been observed with chronic inflammatory conditions of the lung, such as asthma, [41], COPD [42], idiopathic pulmonary fibrosis [43] and interstitial lung diseases [44,45]. …”

Section: Discussionmentioning

confidence: 99%

HEPBURN - investigating the efficacy and safety of nebulized heparin versus placebo in burn patients with inhalation trauma: study protocol for a multi-center randomized controlled trial

Glas

Müller²,

Binnekade

et al. 2014

Trials

View full text Add to dashboard Cite

BackgroundPulmonary coagulopathy is a hallmark of lung injury following inhalation trauma. Locally applied heparin attenuates lung injury in animal models of smoke inhalation. Whether local treatment with heparin benefits patients with inhalation trauma is uncertain. The present trial aims at comparing a strategy using frequent nebulizations of heparin with standard care in intubated and ventilated burn patients with bronchoscopically confirmed inhalation trauma.MethodsThe Randomized Controlled Trial Investigating the Efficacy and Safety of Nebulized HEParin versus Placebo in BURN Patients with Inhalation Trauma (HEPBURN) is an international multi-center, double-blind, placebo-controlled, two-arm study. One hundred and sixteen intubated and ventilated burn patients with confirmed inhalation trauma are randomized to nebulizations of heparin (the nebulized heparin strategy) or nebulizations of normal saline (the control strategy) every four hours for 14 days or until extubation, whichever comes first. The primary endpoint is the number of ventilator-free days, defined as days alive and breathing without assistance during the first 28 days, if the period of unassisted breathing lasts for at least 24 consecutive hours.DiscussionAs far as the authors know, HEPBURN is the first randomized, placebo-controlled trial, powered to investigate whether local treatment with heparin shortens duration of ventilation of intubated and ventilated burn patients with inhalation trauma.Trial registrationNCT01773083 (http://www.clinicaltrials.gov), registered on 16 January 2013.Recruiting. Randomisation commenced on 1 January 2014.

show abstract

“…1,8,9,24,30,36–38 The protective or injurious effects of PAI-1 are mediated not only by its inhibition of plasmin/protease system, but also by PAI-1:vitronectin binding that affects interactions with cell-surface integrins. 17–19 Indeed, recent studies suggest that the pro-fibrotic effects of PAI-1 may be independent of plasmin activity.…”

Section: Discussionmentioning

confidence: 99%

Vitronectin-binding PAI-1 protects against the development of cardiac fibrosis through interaction with fibroblasts

Zhong

Yang

Kon

et al. 2014

Laboratory Investigation

View full text Add to dashboard Cite

Plasminogen activator inhibitor-1 (PAI-1) promotes or abates fibrotic processes occurring in different organs. Binding of PAI-1 to vitronectin, an extracellular matrix component, may inhibit vitronectin–integrin complex-mediated cellular responses in pathophysiological conditions. To investigate the importance of plasmin suppression vs vitronectin-binding pathways of PAI-1 in cardiac fibrosis, we studied uninephrectomized mice fed a high salt diet and infused with angiotensin II (Ang II) together with different PAI-1 variants, including PAI-1AK (AK) that inhibits plasminogen activators but does not bind vitronectin, PAI-1RR (RR) that binds vitronectin but does not have protease inhibitory effects or control PAI-1 (CPAI), the control mutant that has similar molecular backbone and half-life as AK and RR while retaining all functions of native PAI-1. Compared with RR and CPAI, non-vitronectin-binding AK significantly increased expression of cardiac fibroblast marker, periostin (Ang + AK 8.40± 3.55 vs Ang RR 2.23 ± 0.44 and Ang CPAI 2.33 ± 0.12% positive area, both P <0.05) and cardiac fibrosis (Ang + AK 1.79 ± 0.26% vs Ang + RR 0.91 + 0.18% and Ang + CPAI 0.81 ± 0.12% fibrotic area, both P <0.05), as well as Col1 mRNA (Ang + AK 12.81 ± 1.84 vs Ang + RR 4.04 ± 1.06 and Ang + CPAI 5.23 ± 1.21 fold increase, both P <0.05). To elucidate mechanisms underlying the protective effects of vitronectin-binding PAI-1 against fibrosis, fibroblasts from normal adult human ventricles were stimulated with Ang and different PAI-1 variants. Protease inhibitory AK and CPAI increased supernatant fibronectin, while decreasing plasminogen activator/plasmin activities and matrix metalloproteinase. RR and CPAI variants significantly reduced fibroblast expression of integrin β3, vitronectin level in the supernatant and fibroblast adhesion to vitronectin compared with the non-vitronectin-binding AK. Further, RR and CPAI preserved apoptotic, decreased anti-apoptotic and proliferative activities in fibroblasts. Thus, PAI-1 promotes or protects against development of cardiac fibrosis differentially through the protease inhibitory pathway or through its binding to vitronectin.

show abstract

The role of urokinase in idiopathic pulmonary fibrosis and implication for therapy

Cited by 18 publications

References 88 publications

MiR‐10a and miR‐181c regulate collagen type I generation in hypertrophic scars by targeting PAI‐1 and uPA

MiR‐10a and miR‐181c regulate collagen type I generation in hypertrophic scars by targeting PAI‐1 and uPA

HEPBURN - investigating the efficacy and safety of nebulized heparin versus placebo in burn patients with inhalation trauma: study protocol for a multi-center randomized controlled trial

Vitronectin-binding PAI-1 protects against the development of cardiac fibrosis through interaction with fibroblasts

Contact Info

Product

Resources

About