Jorge Boczkowski

University of Paris-Est, La Haye-Descartes, Centre, France

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Publications (242)878.31 Total impact

  • [Show abstract] [Hide abstract] ABSTRACT: Rationale: Sleep disorders may lead to stress-induced premature aging and telomere shortening. Objectives: To determine whether obstructive sleep apnea syndrome causing intermittent hypoxemia episodes was associated with telomere shortening independently from the comorbidities associated with this syndrome. Methods: Cross-sectional study in 161prospectivelly enrolled untreated middle-aged men free of known comorbidities related or unrelated to sleep apnea. Each participant underwent full standard overnight polysomnography. Patients with apnea sleep syndrome were naïve of treatment. Measurements and main results: By univariate analysis, telomere shortening was associated with older age, apnea-hypopnea index, oxygen desaturation index, apnea-hypopnea index, waist circumference, and fat mass. After adjustment for age, only apnea-hypopnea index and oxygen desaturation index were significantly related to telomere shortening. Mean telomere length ratio was 0.70±0.37 in the participants without sleep apnea, compared to 0.61±0.22 and 0.53±0.16 in those with mild-to-moderate and severe sleep apnea, respectively (P=0.01). By multivariate analysis, oxygen desaturation index was the only factor independently associated with telomere length. Arterial stiffness assessed by carotid-femoral pulse wave velocity correlated negatively with telomere length. Conclusions: Intermittent hypoxemia due to obstructive sleep apnea syndrome is a major contributor to telomere shortening in middle-aged males. Oxidative stress may explain this finding.
    No preview · Article · May 2016 · Annals of the American Thoracic Society
  • No preview · Article · Mar 2016 · Médecine du Sommeil
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    [Show abstract] [Hide abstract] ABSTRACT: TCR-dependent and costimulation signaling, cell division, and cytokine environment are major factors driving cytokines expression induced by CD4+ T cell activation. PEA-15 15 (Protein Enriched in Astrocyte / 15kDa) is an adaptor protein that regulates death receptor-induced apoptosis and proliferation signaling by binding to FADD and relocating ERK1/2 to the cytosol, respectively. By using PEA-15-deficient mice, we examined the role of PEA-15 in TCR-dependent cytokine production in CD4+ T cells. TCR-stimulated PEA-15-deficient CD4+ T cells exhibited defective progression through the cell cycle associated with impaired expression of cyclin E and phosphoRb, two ERK1/2-dependent proteins of the cell cycle. Accordingly, expression of the division cycle-dependent cytokines IL-2 and IFNγ, a Th1 cytokine, was reduced in stimulated PEA-15-deficient CD4+ T cells. This was associated with abnormal subcellular compartmentalization of activated ERK1/2 in PEA-15-deficient T cells. Furthermore, in vitro TCR-dependent differentiation of naive CD4+ CD62L+ PEA-15-deficient T cells was associated with a lower production of the Th2 cytokine, IL-4, whereas expression of the Th17-associated molecule IL4I1 was enhanced. Finally, a defective humoral response was shown in PEA-15-deficient mice in a model of red blood cell alloimmunization performed with Poly IC, a classical adjuvant of Th1 response in vivo. Collectively, our data suggest that PEA-15 contributes to the specification of the cytokine pattern of activated Th cells, thus highlighting a potential new target to interfere with T cell functional polarization and subsequent immune response.
    Preview · Article · Aug 2015 · PLoS ONE
  • [Show abstract] [Hide abstract] ABSTRACT: The transcription factor p53 is overexpressed in the lung of patients with emphysema, but it remains unclear if it has a deleterious or protective effect in disease progression. We investigated the role of p53 in the elastase-induced emphysema model and the molecular underlining mechanisms. Wild type (WT) and p53-/- mice were instilled with pancreatic porcine elastase 1UI. We quantified emphysema (morphometric analysis), CCL2 and TNFα in bronchoalveolar lavage (BAL) (ELISA), oxydative stress markers (heme oxygenase 1 (HO1), NAD(P)H dehydrogenase quinone 1 (NQO1) gene expression), MMP12 expression (immunofluorescence), and macrophages apoptosis (cleaved caspase-3 immunofluorescence). p53 gene expression was upregulated in the lung of elastase-instilled mice. p53 deletion aggravated elastase-induced emphysema severity, pulmonary inflammation (macrophages and neutrophils number and CCL2 and TNFa levels in BAL) and lung oxidative stress. These findings were reproduced in WT mice transplanted with p53 -/- bone marrow cells, except the increase in CCL2. The increased number of macrophages in p53 -/- mice was not a consequence of reduced apoptosis or of an excess of chemotaxis toward CCL2. Macrophages expression of MMP12 was higher in p53 -/- mice compared to WT mice after elastase instillation. These findings provide evidence that p53-/- mice and WT mice grafted with p53 -/- myeloid cells are more prone to develop elastase-induced emphysema, supporting a protective role of p53, and more precisely p53 expressed in macrophages, against emphysema development. The pivotal role played by macrophages in this phenomenon may involve the MMP12-TNFα pathway.
    No preview · Article · Jun 2015 · American Journal of Respiratory Cell and Molecular Biology
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    [Show abstract] [Hide abstract] ABSTRACT: Cellular senescence - defined as a stable cell-cycle arrest combined with stereotyped phenotypic changes - might play a causal role in various lung diseases, including chronic obstructive pulmonary disease (COPD), which is predicted to become the third leading cause of death worldwide by 2020. COPD is characterized by slowly progressive airflow obstruction and emphysema due to destruction of the lung parenchyma and is often complicated by pulmonary hypertension (PH). No curative treatment is available. Senescent cells, which accumulate with age, are increased in lungs from patients with COPD and express a robust senescence-associated secretory phenotype (SASP), which is proinflammatory. The aim of this review is to show how senescent cells can drive the lung alterations seen in COPD, which mechanisms may be involved, and whether therapeutic interventions may slow or delay the in vitro cell-senescence process and in vivo lung alterations. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jun 2015 · Pharmacology [?] Therapeutics
  • [Show abstract] [Hide abstract] ABSTRACT: Surface tunability and their ability to translocate plasma membranes make chemically functionalized carbon nanotubes (f-CNTs) promising intracellular delivery systems for therapeutic or diagnostic purposes in the central nervous system (CNS). The present study aimed to determine the biological impact of different types of multi-walled CNTs (MWNTs) on primary neuronal and glial cell populations isolated from foetal rat frontal cortex (FCO) and striatum (ST). Neurons from both brain regions were generally not affected by exposure to MWNTs as determined by a modified LDH assay. In contrast, the viability of mixed glia was reduced in ST-derived mixed glial cultures, but not in FCO-derived ones. Cytotoxicity was independent of MWNT type or dose, suggesting an inherent sensitivity to CNTs. Characterization of the cell populations in mixed glial cultures prior to nanotube exposure showed higher number of CD11b/c positive cells in the ST-derived mixed glial cultures. After exposure to MWNTs, CNT were uptaken more effectively by CD11b/c positive cells (microglia), compared to GFAP positive cells (astrocytes). When exposed to conditioned media from microglia enriched cultures exposed to MWNTs, ST-derived glial cultures secreted more NO than FCO-derived cells. These results suggested that the more significant cytotoxic response obtained from ST-derived mixed glia cultures was related to the higher number of microglial cells in this brain region. Our findings emphasize the role that resident macrophages of the CNS play in response to nanomaterials and the need to thoroughly investigate the brain region-specific effects towards designing implantable devices or delivery systems to the CNS.
    No preview · Article · Jun 2015 · ACS Nano
  • No preview · Article · May 2015 · Acta Physiologica
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    [Show abstract] [Hide abstract] ABSTRACT: Alteration of functional regenerative properties of parenchymal lung fibroblasts is widely proposed as a pathogenic mechanism for chronic obstructive pulmonary disease (COPD). However, what these functions are and how they are impaired in COPD remain poorly understood. Apart from the role of fibroblasts in producing extracellular matrix, recent studies in organs different from the lung suggest that such cells might contribute to repair processes by acting like mesenchymal stem cells. In addition, several reports sustain that the Hedgehog pathway is altered in COPD patients thus aggravating the disease. Nevertheless, whether this pathway is dysregulated in COPD fibroblasts remains unknown. We investigated the stem cell features and the expression of Hedgehog components in human lung fibroblasts isolated from histologically-normal parenchymal tissue from 25 patients-8 non-smokers/non-COPD, 8 smokers-non COPD and 9 smokers with COPD-who were undergoing surgery for lung tumor resection. We found that lung fibroblasts resemble mesenchymal stem cells in terms of cell surface marker expression, differentiation ability and immunosuppressive potential and that these properties were altered in lung fibroblasts from smokers and even more in COPD patients. Furthermore, we showed that some of these phenotypic changes can be explained by an over activation of the Hedgehog signaling in smoker and COPD fibroblasts. Our study reveals that lung fibroblasts possess mesenchymal stem cell-features which are impaired in COPD via the contribution of an abnormal Hedgehog signaling. These processes should constitute a novel pathomechanism accounting for disease occurrence and progression.
    Full-text · Article · Mar 2015 · PLoS ONE
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    [Show abstract] [Hide abstract] ABSTRACT: Chronic obstructive pulmonary disease (COPD) is often associated with age-related systemic abnormalities that adversely affect the prognosis. Whether these manifestations are linked to the lung alterations or are independent complications of smoking remains unclear. To look for aging-related systemic manifestations and telomere shortening in COPD patients and smokers with minor lung destruction responsible for a decline in the diffusing capacity for carbon monoxide (DLCO) corrected for alveolar volume (KCO). Cross-sectional study in 301 individuals (100 with COPD, 100 smokers without COPD, and 101 nonsmokers without COPD). Compared to control smokers, patients with COPD had higher aortic pulse-wave velocity (PWV), lower bone mineral density (BMD) and appendicular skeletal muscle mass index (ASMMI), and shorter telomere length (TL). Insulin resistance (HOMA-IR) and glomerular filtration rate (GFR) were similar between control smokers and COPD patients. Smokers did not differ from nonsmokers for any of these parameters. However, smokers with normal spirometry but low KCO had lower ASMMI values compared to those with normal KCO. Moreover, female smokers with low KCO, had lower BMD and shorter TL compared to those with normal KCO. Aging-related abnormalities in patients with COPD are also found in smokers with minor lung dysfunction manifesting as a KCO decrease. Decreased KCO might be useful, particularly among women, for identifying smokers at high risk for aging-related systemic manifestations and telomere shortening.
    Full-text · Article · Mar 2015 · PLoS ONE
  • E. Paul · J. Rose · J. Boczkowski · S. Lanone · C. Delacourt · J.C. Pairon
    No preview · Article · Mar 2015 · Revue des Maladies Respiratoires
  • V. Cohignac · A. Gerdil · N. Herlin · J. Boczkowski · J.C. Pairon · S. Lanone
    No preview · Article · Mar 2015 · Revue des Maladies Respiratoires
  • No preview · Article · Mar 2015
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    [Show abstract] [Hide abstract] ABSTRACT: -Cells exhibiting dysregulated growth may express telomerase reverse transcriptase (TERT), whose dual function consists in maintaining telomere length, in association with the RNA template molecule TERC and controlling cell growth. Here, we investigated lung TERT in human and experimental pulmonary hypertension (PH) and its role in controlling pulmonary artery-smooth muscle cell (PA-SMC) proliferation. -Marked TERT expression and/or activity were found in lungs from patients with idiopathic PH and from mice with PH induced by hypoxia or serotonin-transporter overexpression (SM22-5HTT+ mice), chiefly within PA-SMCs. In cultured mouse PA-SMCs, TERT was expressed upon growth stimulation by serum. The TERT inhibitor imetelstat and the TERT activator TA65 abrogated and stimulated PA-SMC growth, respectively. PA-SMCs from PH mice showed a heightened proliferative phenotype associated with increased TERT expression, which was suppressed by imetelstat treatment. TERC(-/-) mice at generation 2 (G2) and TERT(-/-) mice at G2, G3, and G4 developed less severe PH than did wild-type mice exposed to chronic hypoxia, with less distal pulmonary-artery muscularization and fewer Ki67-stained proliferating PA-SMCs. Telomere length differed between TERC(-/-) and TERT(-/-) mice, whereas PH severity was similar in the two strains and across generations. Chronic imetelstat treatment reduced hypoxia-induced PH in wild-type mice or partially reversed established PH in SM22-5HTT+ mice, while simultaneously decreasing TERT expression. Opposite effects occurred in mice treated with TA65. -Telomerase exerts telomere-independent effects on PA-SMC growth in PH and may constitute a treatment target for PH.
    Full-text · Article · Dec 2014 · Circulation
  • L Boyer · L Savale · J Boczkowski · S Adnot
    [Show abstract] [Hide abstract] ABSTRACT: The biological mechanisms of aging, and more specifically cellular senescence, are increasingly a subject of research. Cellular senescence may be a common determinant of many age-related diseases, including some chronic lung diseases such as chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis. Many arguments suggest that these diseases are associated with premature senescence of lung cells, which may be involved in the pathophysiology of respiratory alterations. Furthermore, these diseases are associated with systemic manifestations, such as bone loss, muscle wasting and atherosclerosis, which impact on symptoms and prognosis. Whether these alterations are related to a common pathogenic mechanism or develop independently in patients with COPD remains an open question. In this review, we will focus on cellular senescence and COPD. Two concepts will be discussed: (1) the role of cell senescence in the pathophysiology of lung destruction, vascular remodeling and inflammation in COPD, (2) the possible link between the pulmonary and systemic manifestations of COPD which could reflect a general process of accelerated aging. Copyright © 2014 SPLF. Published by Elsevier Masson SAS. All rights reserved.
    No preview · Article · Dec 2014
  • L. Boyer · L. Savale · J. Boczkowski · S. Adnot
    [Show abstract] [Hide abstract] ABSTRACT: Les mécanismes biologiques du vieillissement et plus précisément de la sénescence cellulaire sont l’objet d’une recherche en plein développement. La sénescence cellulaire pourrait constituer un déterminant commun à de nombreuses maladies liées à l’âge et notamment à certaines pathologies pulmonaires chroniques telles la bronchopneumopathie chronique obstructive (BPCO) ou la fibrose pulmonaire idiopathique. De nombreux arguments suggèrent que ces maladies sont associées à une sénescence des cellules pulmonaires qui intervient dans la physiopathologie de l’atteinte respiratoire. De plus, ces pathologies sont associées à des manifestations systémiques, telles la déminéralisation osseuse, la fonte musculaire, l’athérosclérose, qui grèvent le pronostic et dont le mécanisme reste incompris. Dans cette revue, nous nous focaliserons sur la sénescence cellulaire et la BPCO. Deux hypothèses seront abordées : (1) le rôle de la sénescence cellulaire dans la physiopathologie des remaniements pulmonaires, parenchymateux et vasculaires ainsi que dans l’inflammation caractéristique de la maladie ; (2) le lien possible entre les altérations pulmonaires et les manifestations systémiques de la BPCO, qui pourraient traduire un processus général de vieillissement accéléré.
    No preview · Article · Nov 2014 · Revue des Maladies Respiratoires
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    [Show abstract] [Hide abstract] ABSTRACT: We hypothesized that O2 tension influences the redox state and the immunomodulatory responses of inflammatory cells to dimethyl fumarate (DMF), an activator of the nuclear factor Nrf2 that controls antioxidant genes expression. This concept was investigated in macrophages permanently cultured at either physiological (5% O2) or atmospheric (20% O2) oxygen levels and then treated with DMF or challenged with lipopolysaccharide (LPS) to induce inflammation. RAW 264.7 macrophages cultured at 20% O2 exhibited a pro-oxidant phenotype, reflected by a lower content of reduced glutathione, higher oxidized glutathione and increased production of reactive oxygen species when compared to macrophages continuously grown at 5% O2. At 20% O2, DMF induced a stronger antioxidant response compared to 5% O2 as evidenced by a higher expression of heme oxygenase-1, NAD(P)H:quinone oxydoreductase-1 and superoxide dismutase-2. After challenge of macrophages with LPS, several pro-inflammatory (iNOS, TNF-α, MMP-2, MMP-9), anti-inflammatory (arginase-1, IL-10) and pro-angiogenic (VEGF-A) mediators were evaluated in the presence or absence of DMF. All markers, with few interesting exceptions, were significantly reduced at 5% O2. This study brings new insights on the effects of O2 in the cellular adaptation to oxidative and inflammatory stimuli and highlights the importance of characterizing the effects of chemicals and drugs at physiologically relevant O2 tension. Our results demonstrate that the common practice of culturing cells at atmospheric O2 drives the endogenous cellular environment towards an oxidative stress phenotype, affecting inflammation and the expression of antioxidant pathways by exogenous modulators. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Oct 2014 · Journal of Cellular Physiology
  • No preview · Article · Sep 2014 · Revue des Maladies Respiratoires
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    [Show abstract] [Hide abstract] ABSTRACT: The rapid development of nanotechnologies is raising safety concerns because of the potential effects of engineered nanomaterials on human health, particularly at the respiratory level. Since the last decades, many in vivo studies have been interested in the pulmonary effects of different classes of nanomaterials. It has been shown that some of them can induce toxic effects, essentially depending on their physico-chemical characteristics, but other studies did not identify such effects. Inflammation and oxidative stress are currently the two main mechanisms described to explain the observed toxicity. However, the exact underlying mechanism(s) still remain(s) unknown and autophagy could represent an interesting candidate. Autophagy is a physiological process in which cytoplasmic components are digested via a lysosomal pathway. It has been shown that autophagy is involved in the pathogenesis and the progression of human diseases, and is able to modulate the oxidative stress and pro-inflammatory responses. A growing amount of literature suggests that a link between nanomaterial toxicity and autophagy impairment could exist. In this review, we will first summarize what is known about the respiratory effects of nanomaterials and we will then discuss the possible involvement of autophagy in this toxicity. This review should help understand why autophagy impairment could be taken as a promising candidate to fully understand nanomaterials toxicity.
    Full-text · Article · Sep 2014 · Nanomaterials
  • No preview · Article · Sep 2014 · Revue des Maladies Respiratoires
  • [Show abstract] [Hide abstract] ABSTRACT: Introduction Animal Models of Lung Emphysema or Chronic Obstructive Pulmonary Disease Animal Models of Pulmonary Hypertension Animal Models of Fibrotic Lung Diseases Animal Models of Acute Respiratory Distress Syndrome Translation to Clinics: Limitations and Difficulties
    No preview · Chapter · Aug 2014

Publication Stats

5k Citations
878.31 Total Impact Points


  • 2015
    • University of Paris-Est
      La Haye-Descartes, Centre, France
    • Université Paris-Est Créteil Val de Marne - Université Paris 12
      • Faculty of medicine
      Créteil, Île-de-France, France
  • 2000-2013
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2009
    • Hôpital Bichat - Claude-Bernard (Hôpitaux Universitaires Paris Nord Val de Seine)
      Lutetia Parisorum, Île-de-France, France
  • 2008
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France