Papers by Iliana Barbayianni
Decreased ENPP2 mRNA expression in human lung cancer
Clinicopathological characteristics of LC patients with serum samples
ENPP2 is genetically altered in 8% of NSCLC patients, co-amplified with MYC and other 8q24genes
Deregulated genes (S3) and pathways (S4) upon the stochastic deletion of Enpp2 in pulmonary cells
Decreased Enpp2 and Plpp1,3 mRNA expression in animal models of lung cancer
Expression profiling of the ATX/LPA axis in meta-analyzed, publicly available microarray datasets... more Expression profiling of the ATX/LPA axis in meta-analyzed, publicly available microarray datasets of human lung cancer
Pathogenesis and progression of lung cancer are governed by complex interactions between the envi... more Pathogenesis and progression of lung cancer are governed by complex interactions between the environment and host genetic susceptibility, which is further modulated by genetic and epigenetic changes. Autotaxin (ATX, ENPP2) is a secreted glycoprotein that catalyzes the extracellular production of lysophosphatidic acid (LPA), a growth-factor–like phospholipid that is further regulated by phospholipid phosphatases (PLPP). LPA's pleiotropic effects in almost all cell types are mediated through at least six G-protein coupled LPA receptors (LPAR) that exhibit overlapping specificities, widespread distribution, and differential expression profiles. Here we use both preclinical models of lung cancer and clinical samples (from patients and healthy controls) to investigate the expression levels, activity, and biological role of the above components of the ATX/LPA axis in lung cancer. ENPP2 was genetically altered in 8% of patients with lung cancer, whereas increased ATX staining and activ...
Diagnostics
Background: We have previously shown that SHP2 downregulation may predispose fibroblasts to diffe... more Background: We have previously shown that SHP2 downregulation may predispose fibroblasts to differentiate into myofibroblasts and proposed a role for SHP2 downregulation in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Recent data have shown that SHP2 localizes to the mitochondrial intercristae, and its overexpression enhances mitochondrial metabolism leading to oxidative stress and senescence. Objective: To determine the effect of SHP2 on fibrotic responses. Methods and Results: Primary mouse lung fibroblasts derived from mice carrying a conditional knock-in mutation (D61G/+), rendering the SHP2 catalytic domain constitutively active, had reduced proliferation (1.6-fold, p < 0.05), migration (2-fold, p < 0.05), as well as reduced responsiveness of TGFB-1 induced fibroblasts-to-myofibroblasts differentiation, compared to wild-type ones. Electron microscope analysis revealed that SHP2 D61G/+ mouse lung fibroblasts were characterized by mitochondrial abnormalities, in...
The activation and accumulation of lung fibroblasts (LFs), resulting in aberrant deposition of co... more The activation and accumulation of lung fibroblasts (LFs), resulting in aberrant deposition of collagens and other extracellular matrix (ECM) components, is a pathogenic hallmark of Idiopathic Pulmonary Fibrosis (IPF), a lethal and incurable disease. In this report, increased expression of TKS5, a scaffold protein essential for the formation of podosomes, was detected in the lung tissue of IPF patients and bleomycin (BLM)-treated mice, correlating with increased collagen type I alpha 1 chain (COL1A1) expression. The profibrotic milieu, TGFβ, as well as a stiff Col1a1-rich acellular fibrotic ECM, were found to induceTKS5expression and the formation of prominent podosome rosettes in LFs, culminating in increased ECM invasion. Podosomes were retainedex vivoin the absence of any stimulation, indicating that the formation of TKS5-enabled podosomes is an inherent property of IPF LFs. Remarkably, haploinsufficientTks5+/-mice were relatively resistant to BLM-induced pulmonary fibrosis. Dise...
The Journal of Immunology, 2021
Key Points Pulmonary fibrosis entails a transcriptional downregulation of Map3k8 expression. Map3... more Key Points Pulmonary fibrosis entails a transcriptional downregulation of Map3k8 expression. Map3k8 suppress pulmonary fibrosis via Cox-2–mediated PGE2 production. Idiopathic pulmonary fibrosis (IPF) is characterized by exuberant deposition of extracellular matrix components, leading to the deterioration of lung architecture and respiratory functions. Profibrotic mechanisms are controlled by multiple regulatory molecules, including MAPKs, in turn regulated by multiple phosphorylation cascades. MAP3K8 is an MAPK kinase kinase suggested to pleiotropically regulate multiple pathogenic pathways in the context of inflammation and cancer; however, a possible role in the pathogenesis of IPF has not been investigated. In this report, MAP3K8 mRNA levels were found decreased in the lungs of IPF patients and of mice upon bleomycin-induced pulmonary fibrosis. Ubiquitous genetic deletion of Map3k8 in mice exacerbated the modeled disease, whereas bone marrow transfer experiments indicated that al...
BACKGROUND Vitamin D (VitD) is a steroid hormone with cytoprotective and anti-inflammatory proper... more BACKGROUND Vitamin D (VitD) is a steroid hormone with cytoprotective and anti-inflammatory properties. Epidemiological studies have suggested a link between VitD deficiency and risk of development of chronic lung diseases. Its role in lung fibrosis is largely unknown. The aim of our study was to investigate the role of VitD in experimental and human lung fibrosis. METHODS VitD (25-OH-D3, 2 μg/kg) was orally administered from day 3-day 13 following bleomycin-challenge, in 8-10 weeks-old C57/BL6 mice. Mouse Lung Fibroblasts (MLFs) were pre-treated with VitD (2 μM for 24 h) and then stimulated with TGFB1 (10 ng/ml). Serum samples from 93 patients with IPF and other forms of interstitial lung diseases (ILDs) were prospectively collected for VitD measurement. RESULTS VitD administration prevented bleomycin-induced lung fibrosis, as assessed by reductions in hydroxyproline levels, mRNA levels of col1a1, col3a1 and a-SMA (1.4-, 3.1-, 2.25-, 2.5-fold, respectively) and Masson Trichrome stai...
Mechanisms of Lung Injury and Repair
Background: MAP kinase phosphatase 5 (MKP5), is a negative regulator of P38 and JNK and a vitamin... more Background: MAP kinase phosphatase 5 (MKP5), is a negative regulator of P38 and JNK and a vitamin D responsive gene. Recent data demonstrate that MKP5 knockout mice exhibit improved muscle repair with minimal fibrosis in an animal model of muscular dystrophy. Aim: We aimed to determine the role of MKP5 in experimental lung fibrosis Methods and results: MKP5 knockout mice (MKP5-/-) were protected from bleomycin-induced lung fibrosis as indicated by reduced hydroxyproline levels (3-fold, p Conclusion: We conclude that intact MKP5 is required for induction of changes in lung fibroblasts in-vitro and during bleomycin-induced lung fibrosis in-vivo. Our results couple MKP5 activity with TGFB1 signaling machinery identifying MKP5 inhibition as a promising therapeutic strategy for experimental and human lung fibrosis.
Idiopathic interstitial pneumonias
Frontiers in Medicine, 2018
Idiopathic Pulmonary Fibrosis (IPF) is a fatal disease characterized by exuberant deposition of e... more Idiopathic Pulmonary Fibrosis (IPF) is a fatal disease characterized by exuberant deposition of extracellular matrix components, deterioration of lung architecture and impairment of lung functions. Its etiopathogenesis remains incompletely understood, as reflected in the lack of an appropriate therapy. Modeling the human disease in mice via the administration of bleomycin (BLM), despite the inherent limitations, has provided valuable insights into the underlying pathogenetic mechanisms, and has been instrumental for the development and validation of new pharmacologic interventions. Here we have directly compared the, most widely used, intratracheal (IT) route of administration with oropharyngeal aspiration (OA). Our results suggest that the OA route of BLM-administration can be used as a safe and effective alternative, minimizing peri-operative and experimental mortality, while preserving a solid fibrotic profile, as assessed with a plethora of standardized readout assays.
Frontiers in Medicine
Chronic lung diseases represent complex diseases with gradually increasing incidence, characteriz... more Chronic lung diseases represent complex diseases with gradually increasing incidence, characterized by significant medical and financial burden for both patients and relatives. Their increasing incidence and complexity render a comprehensive, multidisciplinary, and personalized approach critically important. This approach includes the assessment of comorbid conditions including metabolic dysfunctions. Several lines of evidence show that metabolic comorbidities, including diabetes mellitus, dyslipidemia, osteoporosis, vitamin D deficiency, and thyroid dysfunction have a significant impact on symptoms, quality of life, management, economic burden, and disease mortality. Most recently, novel pathogenetic pathways and potential therapeutic targets have been identified through large-scale studies of metabolites, called metabolomics. This review article aims to summarize the current state of knowledge on the prevalence of metabolic comorbidities in chronic lung diseases, highlight their impact on disease clinical course, delineate mechanistic links, and report future perspectives on the role of metabolites as disease modifiers and therapeutic targets.
Cancer research, 2018
Pathogenesis and progression of lung cancer are governed by complex interactions between the envi... more Pathogenesis and progression of lung cancer are governed by complex interactions between the environment and host genetic susceptibility, which is further modulated by genetic and epigenetic changes. Autotaxin (ATX, ENPP2) is a secreted glycoprotein that catalyzes the extracellular production of lysophosphatidic acid (LPA), a growth-factor-like phospholipid that is further regulated by phospholipid phosphatases (PLPP). LPA's pleiotropic effects in almost all cell types are mediated through at least six G-protein coupled LPA receptors (LPAR) that exhibit overlapping specificities, widespread distribution, and differential expression profiles. Here we use both preclinical models of lung cancer and clinical samples (from patients and healthy controls) to investigate the expression levels, activity, and biological role of the above components of the ATX/LPA axis in lung cancer. was genetically altered in 8% of patients with lung cancer, whereas increased ATX staining and activity we...
Cancer Research
Pathogenesis and progression of lung cancer are governed by complex interactions between the envi... more Pathogenesis and progression of lung cancer are governed by complex interactions between the environment and host genetic susceptibility, which is further modulated by genetic and epigenetic changes. Autotaxin (ATX, ENPP2) is a secreted glycoprotein that catalyzes the extracellular production of lysophosphatidic acid (LPA), a growth-factor-like phospholipid that is further regulated by phospholipid phosphatases (PLPP). LPA's pleiotropic effects in almost all cell types are mediated through at least six G-protein coupled LPA receptors (LPAR) that exhibit overlapping specificities, widespread distribution, and differential expression profiles. Here we use both preclinical models of lung cancer and clinical samples (from patients and healthy controls) to investigate the expression levels, activity, and biological role of the above components of the ATX/LPA axis in lung cancer. ENPP2 was genetically altered in 8% of patients with lung cancer, whereas increased ATX staining and activity were detected in patient biopsies and sera, respectively. Moreover, PLPP3 expression was consistently downregulated in patients with lung cancer. Comparable observations were made in the two most widely used animal models of lung cancer, the carcinogen urethane-induced and the genetically engineered K-ras G12D-driven models, where genetic deletion of Enpp2 or Lpar1 resulted in disease attenuation, thus confirming a procarcinogenic role of LPA signaling in the lung. Expression profiling data analysis suggested that metabolic rewiring may be implicated in the procarcinogenic effects of the ATX/LPA axis in K-ras-G12D-driven lung cancer pathogenesis. Significance: These findings establish the role of ATX/LPA in lung carcinogenesis, thus expanding the mechanistic links between pulmonary fibrosis and cancer. Cancer Res; 78(13); 3634-44.
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Papers by Iliana Barbayianni