Jorge Boczkowski

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

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Publications (195)806.34 Total impact

  • [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.
    American Journal of Respiratory Cell and Molecular Biology 06/2015; DOI:10.1165/rcmb.2014-0375OC · 4.11 Impact Factor
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    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.
    Pharmacology [?] Therapeutics 06/2015; DOI:10.1016/j.pharmthera.2015.06.007 · 7.75 Impact Factor
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    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.
    ACS Nano 06/2015; DOI:10.1021/acsnano.5b02358 · 12.88 Impact Factor
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    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.
    PLoS ONE 03/2015; 10(3):e0121579. DOI:10.1371/journal.pone.0121579 · 3.23 Impact Factor
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    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.
    PLoS ONE 03/2015; 10(3):e0121539. DOI:10.1371/journal.pone.0121539 · 3.23 Impact Factor
  • E. Paul · J. Rose · J. Boczkowski · S. Lanone · C. Delacourt · J.C. Pairon
    Revue des Maladies Respiratoires 03/2015; 32(3):334-335. DOI:10.1016/j.rmr.2015.02.074 · 0.49 Impact Factor
  • V. Cohignac · A. Gerdil · N. Herlin · J. Boczkowski · J.C. Pairon · S. Lanone
    Revue des Maladies Respiratoires 03/2015; 32(3):334. DOI:10.1016/j.rmr.2015.02.073 · 0.49 Impact Factor
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    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.
    Circulation 12/2014; 131(8). DOI:10.1161/CIRCULATIONAHA.114.013258 · 14.95 Impact Factor
  • L Boyer · L Savale · J Boczkowski · S Adnot
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    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.
  • L. Boyer · L. Savale · J. Boczkowski · S. Adnot
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    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.
    Revue des Maladies Respiratoires 11/2014; 31(10). DOI:10.1016/j.rmr.2014.07.015 · 0.49 Impact Factor
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    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.
    Journal of Cellular Physiology 10/2014; 230(5). DOI:10.1002/jcp.24844 · 3.87 Impact Factor
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    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.
    Nanomaterials 09/2014; 4(3):548-582. DOI:10.3390/nano4030548 · 2.08 Impact Factor
  • Revue des Maladies Respiratoires 09/2014; 31(7):655. DOI:10.1016/j.rmr.2014.04.025 · 0.49 Impact Factor
  • Revue des Maladies Respiratoires 09/2014; 31(7):660–661. DOI:10.1016/j.rmr.2014.04.037 · 0.49 Impact Factor
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    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
    08/2014: pages 431-448;
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    ABSTRACT: Manufactured nanomaterials (MNMs) have the potential to improve everyday life as they can be utilised in numerous medical applications and day-to-day consumer products. However, this increased use has led to concerns about the potential environmental and human health impacts. The protein p53 is a key transcription factor implicated in cellular defence and reparative responses to various stress factors. Additionally, p53 has been implicated in cellular responses following exposure to some MNMs. Here, the role of the MNM mediated p53 induction and activation and its downstream effects following exposure to five well-characterised materials [namely two types of TiO2, two carbon black (CB), and one single-walled carbon nanotube (SWCNT)] were investigated. MNM internalisation, cellular viability, p53 protein induction and activation, oxidative stress, inflammation and apoptosis were measured in murine cell line and primary pulmonary macrophage models. It was observed that p53 was implicated in the biological responses to MNMs, with oxidative stress associated with p53 activation (only following exposure to the SWCNT). We demonstrate that p53 acted as an antioxidant and anti-inflammatory in macrophage responses to SWCNT and CB NMs. However, p53 was neither involved in MNM-induced cellular toxicity, nor in the apoptosis induced by these MNMs. Moreover, the physicochemical characteristics of MNMs seemed to influence their biological effects-SWCNT the materials with the largest surface area and a fibrous shape were the most cytotoxic in this study and were capable of the induction and activation of p53.
    Archive für Toxikologie 08/2014; DOI:10.1007/s00204-014-1324-5 · 5.08 Impact Factor
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    ABSTRACT: BackgroundAlthough major concerns exist regarding the potential consequences of human exposure to nanoparticles (NP), no human toxicological data is currently available. To address this issue, we took welders, who present various adverse respiratory outcomes, as a model population of occupational exposure to NP.The aim of this study was to evaluate if welding fume-issued NP could be responsible, at least partially, in the lung alterations observed in welders.MethodsA combination of imaging and material science techniques including ((scanning) transmission electron microscopy ((S)TEM), energy dispersive X-ray (EDX), and X-ray microfluorescence (μXRF)), was used to characterize NP content in lung tissue from 21 welders and 21 matched control patients. Representative NP were synthesized, and their effects on macrophage inflammatory secretome and migration were evaluated, together with the effect of this macrophage inflammatory secretome on human lung primary fibroblasts differentiation.ResultsWelding-related NP (Fe, Mn, Cr oxides essentially) were identified in lung tissue sections from welders, in macrophages present in the alveolar lumen and in fibrous regions. In vitro macrophage exposure to representative NP (Fe2O3, Fe3O4, MnFe2O4 and CrOOH) induced the production of a pro-inflammatory secretome (increased production of CXCL-8, IL-1ß, TNF-α, CCL-2, −3, −4, and to a lesser extent IL-6, CCL-7 and −22), and all but Fe3O4 NP induce an increased migration of macrophages (Boyden chamber). There was no effect of NP-exposed macrophage secretome on human primary lung fibroblasts differentiation.ConclusionsAltogether, the data reported here strongly suggest that welding-related NP could be responsible, at least in part, for the pulmonary inflammation observed in welders. These results provide therefore the first evidence of a link between human exposure to NP and long-term pulmonary effects.
    Particle and Fibre Toxicology 05/2014; 11(1):23. DOI:10.1186/1743-8977-11-23 · 6.99 Impact Factor
  • Revue des Maladies Respiratoires 01/2014; 31:A194-A195. DOI:10.1016/j.rmr.2013.10.128 · 0.49 Impact Factor
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    ABSTRACT: Abstract Engineered nanoparticles are increasingly used in medical applications and day-to-day consumer products, leading to concerns about the potential environmental and human health impacts. Silver nanoparticles are particularly prevalent because of their use as anti-bacterial agents in many commonly available products. Nanoparticles (NPs) are believed to accumulate, often preferentially, in the liver. This study therefore investigates the effect of a silver NP (20 nm) on the liver, and in particular, the role of Kupffer cells (KCs; resident liver macrophages) in the overall inflammatory response in the organ. Cytokine expression in the normal liver was measured in terms of IL2, IL4, TNF-α, IFN-γ and IL10 released from the organ with significant up-regulation of TNF-α and IL10 being observed. For livers in which the KC population was specifically targeted and destroyed this cytokine increase was significantly decreased in comparison to the normal tissue. IL10 was secreted at approximately three times the concentration of TNF-α in all the test cases. The high levels of IL10 released from the normal tissue in comparison to the KC depleted livers suggest that the cytokine may help to protect against a pro-inflammatory response to these Ag NPs. This may indicate a potentially important role for KCs in the anti-inflammatory response and suggests that tolerance to the Ag NPs is favoured over a fully activated immune response. In addition, albumin production was measured as an indicator of hepatic function. It was noted that the liver function was unaffected by the Ag NPs.
    Nanotoxicology 12/2013; 8(S1). DOI:10.3109/17435390.2013.866284 · 7.34 Impact Factor
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    ABSTRACT: Carbon monoxide-releasing molecules (CORMs) represent a pharmacological alternative to CO gas inhalation. Here, we questioned whether CORM-3, a well-characterized water-soluble CORM, could prevent and reverse pulmonary hypertension (PH) in chronically hypoxic mice and in smooth muscle promoter 22 serotonin transporter mice overexpressing the serotonin transporter in smooth muscle cells (SMCs). Treatment with CORM-3 (50 mg/kg per day once daily) for 3 weeks prevented PH, right ventricular hypertrophy, and distal pulmonary artery muscularization in mice exposed to chronic hypoxia and partially reversed PH in smooth muscle promoter 22 serotonin transporter mice by reducing Ki67 dividing pulmonary artery SMCs (PA-SMCs). In these models, CORM-3 markedly increased lung p21 mRNA and protein levels and p21-stained PA-SMCs. These effects contrasted with the transient pulmonary vasodilatation and rise in lung cGMP levels induced by a single injection of CORM-3 in mice exposed to acute hypoxia. Studies in cultured rat PA-SMCs revealed that the inhibitory effects of CORM-3 on cell growth were independent of cGMP formation but associated with increased p21 mRNA and protein levels. Protection against PH by CORM-3 required increased lung expression of p21, as indicated by the inability of CORM-3 to prevent chronic hypoxia-induced PH in p21-deficient mice and to alter the growth of PA-SMCs derived from p21-deficient mice. CORM-3-induced p21 overexpression was linked to p53 activation as assessed by the inability of CORM-3 to prevent PH and induce p21 expression in p53-deficient mice and in PA-SMCs derived from p53-deficient mice. CORM-3 inhibits pulmonary vascular remodeling via p21, which may represent a useful approach for treating PH.
    Arteriosclerosis Thrombosis and Vascular Biology 12/2013; 34(2). DOI:10.1161/ATVBAHA.113.302302 · 5.53 Impact Factor

Publication Stats

4k Citations
806.34 Total Impact Points

Institutions

  • 2010–2015
    • University of Paris-Est
      La Haye-Descartes, Centre, France
  • 2009–2015
    • Université Paris-Est Créteil Val de Marne - Université Paris 12
      • Faculty of medicine
      Créteil, Île-de-France, France
    • Institut national de l'environnement industriel et des risques
      Verneuil, Picardie, France
  • 1994–2013
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 1994–2012
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2011
    • Centre Hospitalier Intercommunal Creteil
      Créteil, Île-de-France, France
  • 2006–2010
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
    • Cheikh Anta Diop University, Dakar
      Dakar, Dakar, Senegal
  • 2007–2009
    • Paris Diderot University
      Lutetia Parisorum, Île-de-France, France
  • 2006–2009
    • Hôpital Bichat - Claude-Bernard (Hôpitaux Universitaires Paris Nord Val de Seine)
      Lutetia Parisorum, Île-de-France, France
  • 2008
    • Jagiellonian University
      • Faculty of Biochemistry, Biophysics and Biotechnology
      Cracovia, Lesser Poland Voivodeship, Poland
  • 1999
    • University of Buenos Aires
      Buenos Aires, Buenos Aires F.D., Argentina