Role of Plasminogen Activator Inhibitor-1 in Senescence and Aging

McKay-Corkum

International Journal of Radiation Oncology*Biology*Physics

et al. 2016

Purpose/Objectives Fibrosis is a late toxicity of thoracic irradiation that can result in substantial morbidity. Plasminogen activator inhibitor-1 (PAI-1) is a critical mediator of cellular senescence and fibrin stabilization. We sought to determine if the delivery of recombinant truncated PAI-1 protein (rPAI-123) would protect from the development of radiation-induced lung injury. Methods and Materials C57Bl/6 mice received intraperitoneal injections of rPAI-123 (5.4 μg/kg/day) or vehicle for 18 weeks beginning two days prior to radiation exposure (5 daily fractions of 6 Gy). Cohorts of mice were followed for survival (n=8 per treatment) and tissue collection (n=3 per treatment and time point). Fibrosis in lung was assessed with Masson-Trichrome staining and measurement of hydroxyproline content. Senescence was assessed with staining for beta-galactosidase activity in lung and primary pneumocytes. Results Hydroxyproline content in irradiated lung was significantly reduced in mice that received rPAI-123 compared to mice that received vehicle (IR+vehicle: 84.97, IR+rPAI-123: 56.2 μg/lung, p=0.001). C57Bl/6 mice exposed to IR+vehicle had dense foci of subpleural fibrosis at 19 weeks, whereas the lungs of mice exposed to IR+rPAI-123 were largely devoid of fibrotic foci. Cellular senescence was significantly decreased by rPAI-123 treatment in primary pneumocyte cultures and in lung at multiple time points after IR. Conclusions These studies identify that rPAI-123 is capable of preventing radiation-induced fibrosis in murine lungs. These anti-fibrotic effects are associated with increased fibrin metabolism, enhanced matrix metalloproteinase-3 (MMP-3) expression and reduced senescence in type II pneumocytes. rPAI-123 is a novel therapeutic option for radiation-induced fibrosis.

Section: Resultsmentioning

confidence: 99%

Truncated Plasminogen Activator Inhibitor-1 Protein Protects From Pulmonary Fibrosis Mediated by Irradiation in a Murine Model

McKay-Corkum

International Journal of Radiation Oncology*Biology*Physics

et al. 2016

Journal of the American College of Surgeons

“…We also appreciated an increase in age was associated with an increase in the fibrinolysis shutdown phenotype. PAI-1 levels have been associated with physiologic aging and disease processes(49). It remains unclear if these elderly patients do poorly following trauma because they are predisposed to fibrinolysis resistance, or from other physiologic derangements from advanced aged.…”

Section: Discussionmentioning

confidence: 99%

Acute Fibrinolysis Shutdown after Injury Occurs Frequently and Increases Mortality: A Multicenter Evaluation of 2,540 Severely Injured Patients

Moore

Liras

et al. 2016

254

263

Background Fibrinolysis is a physiologic process to maintain microvascular patency by breaking down excessive fibrin clot. Hyperfibrinolysis (HF) is associated with a doubling of mortality. Fibrinolysis shutdown (SD), an acute impairment of fibrinolysis, has been recognized as a risk factor for increased mortality. The purpose of this study was to assess the incidence and outcomes of fibrinolysis phenotypes in two urban trauma centers. Study Design Injured patients admitted 2010-2013, who were ≥18 years of age, had an injury severity score (ISS) >15 were included in the analysis. Admission fibrinolysis phenotypes were determined by the clot lysis at 30 minutes (LY30): SD ≤0.8%, physiologic 0.9-2.9%, HF ≥3%. Logistic regression was used to adjust for age, arrival blood pressure, ISS, mechanism, and facility. Results 2540 patients met inclusion. Median age was 39(IQR 26-55) and median ISS was 25(IQR 20-33) with a mortality rate of 21%. Fibrinolysis shutdown was the most common phenotype (46%) followed by physiologic (36%) and hyperfibrinolysis(18%). HF was associated with the highest death rate (34%), followed by SD(22%), and physiologic (14%, p<0.001). The risk of mortality remained increased for HF(OR=3.3, 95%C: 2.4-4.6, p<0.0001) and SD(OR 1.6 95%CI 1.3-2.1, p=0.0003) compared to physiologic when adjusting for age, ISS, mechanism, head injury, and blood pressure (AUROC=0.82, 95% CI 0.80-0.84). Conclusions Fibrinolysis SD is the most common phenotype upon admission and is associated with increased mortality. Moreover, these data provide additional evidence of distinct phenotypes of coagulation impairment and that individualized hemostatic therapy may be required.

Experimental Gerontology

“…Mice based on a PAI-1 promoter-suicide gene construct may be informative, since PAI-1 has been implicated in inducing cellular senescence and spread of senescence from cell to cell (Eren et al, 2014a). Recently, PAI-1 inhibitors have been shown to extend lifespan in progeroid Klotho -deficient mice in tandem with decreased senescent cell burden (Eren et al, 2014b), implicating PAI-1 in the genesis, spread, or viability of senescent cells.…”

Section: Animal Models Of Cellular Senescence-associated Diseasesmentioning

confidence: 99%

Clinical strategies and animal models for developing senolytic agents

Kirkland

Tchkonia

2015

129

110

Aging is associated with increasing predisposition to multiple chronic diseases. One fundamental aging process that is often operative at sites of the pathology underlying chronic age-related diseases is cellular senescence. Small molecule senolytic agents are being developed. For successful drug development: 1) appropriate animal models of human age-related diseases need to be devised. 2) Models have to be made in which it can be proven that beneficial phenotypic effects are actually caused through clearing senescent cells by putative senolytic agents, as opposed to “off-target” effects of these agents on non-senescent cells. 3) Models are needed to test efficacy of drugs and to uncover potential side effects of senolytic agents. Development of the optimal animal models and clinical trial paradigms for senolytic agents warrants an intensive effort, since senolytic agents, if successful in delaying, preventing, alleviating, or reversing age-related diseases as a group would be transformative.