Precision targeting of the plasminogen activator inhibitor‐1 mechanism increases efficacy of fibrinolytic therapy in empyema

Florova, Galina; Girard, R.; Azghani, Ali; Sarva, Krishna; Buchanan, Ann M.; Karandashova, Sophia; DeVera, Christian J.; Morris, D.E.; Chamiso, Mignote; Koenig, Kathleen; Cines, Douglas B.; Idell, Steven; Komissarov, Andrey A.

doi:10.14814/phy2.14861

Cited by 5 publications

(48 citation statements)

References 46 publications

(138 reference statements)

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“…Thus, clinical trials can be best informed by preclinical testing to define approaches to selecting treatment strategies that would account for disease severity as well as overall patient health and comorbidities. Targeting the mechanisms of a serpin, plasminogen activator inhibitor 1 (PAI-1), with monoclonal antibodies (mAbs) or a small Docking Site Peptide (DSP) resulted in an up to eight fold decrease in the effective bolus dose of plasminogen activator in rabbit models of chemically induced pleural injury and acute streptococcal empyema ( Florova et al, 2015 ; Florova et al, 2018 ; Florova et al, 2021 ) without an increase in bleeding. Thus, PAI-1-targeted fibrinolytic therapy (PAI-1-TFT) aiming to support effective intrapleural fibrinolysis with low doses of tPA or uPA could become a novel approach to increasing the efficacy of treatment and decreasing the risk of bleeding complications in patients with empyema.…”

Section: Bleeding Complications: Comparison Of the Efficacy And Safety Of Tpa And Upamentioning

confidence: 99%

“…A novel biomarker, Fibrinolytic Potential (FP) was identified in preclinical studies and may address this issue ( Florova et al, 2015 ; Komissarov et al, 2016 ; Idell et al, 2017 ; Florova et al, 2018 ; Beckert et al, 2019 ; Florova et al, 2021 ). Plasminogen accumulates in the pleural fluid of patients with empyema due to inhibited plasminogen activation.…”

Section: A New Point Of Care Test For Predicting the Outcome Of Ipftmentioning

confidence: 99%

“…These clinical studies strongly call for translational research guiding the development of effective, less invasive treatments for patients with advanced stage empyema, who are unable to receive VATS or thoracoscopic surgery. Patients that decline or are unfit for surgical intervention could potentially benefit from treatment with low dose PAI-1-TFT, which allows for a decrease in the dose of plasminogen activator by almost an order of magnitude ( Florova et al, 2015 ; Florova et al, 2018 ; Florova et al, 2021 ) or treatment with innovative encapsulated plasminogen activators in combination with ultrasound, which is successfully used in circulation ( Bader et al, 2015 ; Klegerman et al, 2016 ; Klegerman, 2017 ; Miao et al, 2018 ). Any improvement in non-surgical drainage by decreasing the dose of the plasminogen activator, increasing the rate of intrapleural fibrinolysis, or increasing the half-life of plasminogen activating and fibrinolytic activities could positively affect the survival of this patient population.…”

Section: Recent Approaches To Treat Empyema Patients With Surgical Contraindicationsmentioning

confidence: 99%

“…Over the last decade, the major mechanisms of intrapleural fibrinolysis identified in rabbit models of chemical and infectious pleural injury were also observed in humans ( Komissarov et al, 2009 ; Komissarov et al, 2011 ; Karandashova et al, 2013 ; Komissarov et al, 2013 ; Florova et al, 2015 ; Komissarov et al, 2016 ; Florova et al, 2018 ; Idell and Rahman, 2018 ; Komissarov et al, 2018 ; Beckert et al, 2019 ). This resulted in identification and validation of PAI-1 as a molecular target ( Karandashova et al, 2013 ) and development of PAI-1-TFT, which allows for an up to 8-fold decrease in the dose of plasminogen activator ( Florova et al, 2015 ; Florova et al, 2018 ; Florova et al, 2021 ), as well as FP, a novel biomarker for assessing the likelihood of failure of IPFT in an individual patient ( Florova et al, 2015 ; Komissarov et al, 2016 ; Idell et al, 2017 ; Florova et al, 2018 ; Beckert et al, 2019 ; Florova et al, 2021 ).…”

Section: Validated Animal Models Are Needed For Successful Preclinical Studiesmentioning

confidence: 99%

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From Bedside to the Bench—A Call for Novel Approaches to Prognostic Evaluation and Treatment of Empyema

et al. 2022

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Empyema, a severe complication of pneumonia, trauma, and surgery is characterized by fibrinopurulent effusions and loculations that can result in lung restriction and resistance to drainage. For decades, efforts have been focused on finding a universal treatment that could be applied to all patients with practice recommendations varying between intrapleural fibrinolytic therapy (IPFT) and surgical drainage. However, despite medical advances, the incidence of empyema has increased, suggesting a gap in our understanding of the pathophysiology of this disease and insufficient crosstalk between clinical practice and preclinical research, which slows the development of innovative, personalized therapies. The recent trend towards less invasive treatments in advanced stage empyema opens new opportunities for pharmacological interventions. Its remarkable efficacy in pediatric empyema makes IPFT the first line treatment. Unfortunately, treatment approaches used in pediatrics cannot be extrapolated to empyema in adults, where there is a high level of failure in IPFT when treating advanced stage disease. The risk of bleeding complications and lack of effective low dose IPFT for patients with contraindications to surgery (up to 30%) promote a debate regarding the choice of fibrinolysin, its dosage and schedule. These challenges, which together with a lack of point of care diagnostics to personalize treatment of empyema, contribute to high (up to 20%) mortality in empyema in adults and should be addressed preclinically using validated animal models. Modern preclinical studies are delivering innovative solutions for evaluation and treatment of empyema in clinical practice: low dose, targeted treatments, novel biomarkers to predict IPFT success or failure, novel delivery methods such as encapsulating fibrinolysin in echogenic liposomal carriers to increase the half-life of plasminogen activator. Translational research focused on understanding the pathophysiological mechanisms that control 1) the transition from acute to advanced-stage, chronic empyema, and 2) differences in outcomes of IPFT between pediatric and adult patients, will identify new molecular targets in empyema. We believe that seamless bidirectional communication between those working at the bedside and the bench would result in novel personalized approaches to improve pharmacological treatment outcomes, thus widening the window for use of IPFT in adult patients with advanced stage empyema.

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Section: Bleeding Complications: Comparison Of the Efficacy And Safety Of Tpa And Upamentioning

confidence: 99%

Section: A New Point Of Care Test For Predicting the Outcome Of Ipftmentioning

confidence: 99%

Section: Recent Approaches To Treat Empyema Patients With Surgical Contraindicationsmentioning

confidence: 99%

Section: Validated Animal Models Are Needed For Successful Preclinical Studiesmentioning

confidence: 99%

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From Bedside to the Bench—A Call for Novel Approaches to Prognostic Evaluation and Treatment of Empyema

et al. 2022

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“…PAI-1-targeted fibrinolytic therapy (PAI-1TFT) is designed to decrease the effective dose of a fibrinolysin by protecting intrapleural plasminogen activating activity from PAI-1, thereby rendering otherwise ineffective doses of plasminogen activator effective. Our results demonstrate that targeting the PAI-1 mechanism increases the efficacy of single chain (sc) tPA (Alteplase) and scuPA in rabbit models of chemically induced pleural injury and acute, early-stage empyema to 8-fold [ 39 , 40 , 41 ]. S. pneumoniae induced empyema in rabbits [ 41 , 42 ] recapitulates the key features of empyema observed in humans, including the progression from an acute, early stage to a more advanced chronic one, accompanied by increasing pleural fibrosis, loculation, and pleural thickening ( Figure 1 , panel (a)).…”

Section: Introductionmentioning

confidence: 99%

Targeting the PAI-1 Mechanism with a Small Peptide Increases the Efficacy of Alteplase in a Rabbit Model of Chronic Empyema

et al. 2023

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The incidence of empyema is increasing and associated with a mortality rate of 20% in patients older than 65 years. Since 30% of patients with advanced empyema have contraindications to surgical treatment, novel, low-dose, pharmacological treatments are needed. A Streptococcus pneumoniae-induced rabbit model of chronic empyema recapitulates the progression, loculation, fibrotic repair, and pleural thickening of human disease. Treatment with single chain (sc) urokinase (scuPA) or tissue type (sctPA) plasminogen activators in doses 1.0–4.0 mg/kg were only partially effective in this model. Docking Site Peptide (DSP; 8.0 mg/kg), which decreased the dose of sctPA for successful fibrinolytic therapy in acute empyema model did not improve efficacy in combination with 2.0 mg/kg scuPA or sctPA. However, a two-fold increase in either sctPA or DSP (4.0 and 8.0 mg/kg or 2.0 and 16.0 mg/kg sctPA and DSP, respectively) resulted in 100% effective outcome. Thus, DSP-based Plasminogen Activator Inhibitor 1-Targeted Fibrinolytic Therapy (PAI-1-TFT) of chronic infectious pleural injury in rabbits increases the efficacy of alteplase rendering ineffective doses of sctPA effective. PAI-1-TFT represents a novel, well-tolerated treatment of empyema that is amenable to clinical introduction. The chronic empyema model recapitulates increased resistance of advanced human empyema to fibrinolytic therapy, thus allowing for studies of muti-injection treatments.

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Designing rt-PA Analogs to Release its Trapped Thrombolytic Activity

2021

J. Comput. Biophys. Chem.

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Recombinant tissue-type plasminogen activator (rt-PA, alteplase) is an FDA-approved thrombolytic drug. Designing rt-PA analogs to suppress its inhibition by plasminogen activator inhibitor-1 (PAI-1) without compromising its pharmacological activity has been a continued effort because rt-PA is rapidly inactivated by endogenous PAI-1, leading to the thrombolytic activity of rt-PA being trapped by endogenous PAI-1. Here, incorporating currently available structure of the rt-PA-PAI-1 Michaelis complex structures, this paper uncovers the interstructural biophysics underlying the rt-PA-PAI-1 binding interface, and puts forward a structural biophysical basis for the design of a previously reported rt-PA analogue (T103N, N117Q, KHRR (296-299) AAAA). In addition, this paper proposes a set of rt-PA analogs with lower or higher affinity to PAI-1, including rt-PA (alanine scanning for E_60A, D_189 and R_39), rt-PA (Q60E) and rt-PA (Q60E-F150H-Y151K), towards the release of the trapped thrombolytic activity of rt-PA, and also in the hope that there is still room for the improvement of the efficacy-safety balance of rt-PA in future.

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Precision targeting of the plasminogen activator inhibitor‐1 mechanism increases efficacy of fibrinolytic therapy in empyema

Cited by 5 publications

References 46 publications

From Bedside to the Bench—A Call for Novel Approaches to Prognostic Evaluation and Treatment of Empyema

From Bedside to the Bench—A Call for Novel Approaches to Prognostic Evaluation and Treatment of Empyema

Targeting the PAI-1 Mechanism with a Small Peptide Increases the Efficacy of Alteplase in a Rabbit Model of Chronic Empyema

Designing rt-PA Analogs to Release its Trapped Thrombolytic Activity

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