Physiopathology of COPD and other respiratory consequences of environmental particle inhalation

 

thematiqueResearch theme:

 

Environmental assault, whether occupational or not, play a central role in the etiology of several respiratory diseases, such as Chronic Obstructive Pulmonary Disease (COPD). This represents a true public health issue, especially as news particular contaminants, nanoparticles (NP), arise those later years, accompanied by incompletely characterized effects on health. Overall, our team is interested in studying the respiratory consequences of environmental particle inhalation, with a particular focus on 1/the role of cellular senescence in the physiopathology of post-tobacco and/or occupational COPD; 2/ the respiratory consequences of exposure to anthropic NP, seeking a link between physico-chemical properties of NP and their biological effects on lungs; and 3/ early origins of COPD and other respiratory consequences to environmental particle exposure.

 

Main results:

Thanks to a translational approach based on the set-up of patient cohorts thoroughly characterized in terms of phenotype and exposure, as well as cellular studies and murine models of COPD, cigarette and/or NP exposure, we were able to obtain the following significant results those past years:

 

1/ p53 protein, a major actor of cellular senescence, plays a role in the inflammatory and oxidative response of alveolar macrophages in murine models of COPD and murine models of exposure to manufactured nanoparticles (AJRCMB 2016, Arch Toxicol 2014);

2/ Prostaglandin E2 (PGE2) plays a major role in the induction and preservation of cellular senescence and inflammation associated to COPD via mechanisms implying prostaglandin receptors EP2 and EP4, COX2-dependent oxygen free radicals production, and p53 pathway activation (AJRCCM 2013);

3/ NP physico-chemical characteristics such as diameter, length, surface properties or chemical nature are critical determinants of their pulmonary inflammatory and oxidative effects, as well as their intracellular modification (Particle & Fibre Toxicol 2016, 2013, 2011, 2010, AJRCMB 2013, Nanoletters 2008);

4/ Metal NP (Fe, Cr, and Mn essentially) are present in the lung tissue of welders and potentially play a role in the lung fibrosis observed in these patients (Nanotoicology 2016, Particle & Fibre Toxicol 2014);

5/ Maternal exposure, during gestation, to cigarette smoke induces a significant lung function impairment at adolescence, as well as a susceptibility to reexposure to cigarette smoke at adolescence. This suggest that prenatal and adolescent exposure to cigarette smoke have a synergistic effect on lung function in mice (Environment Health Perspect 2016).

 

This work has been performed thanks to the strong involvement of MDs (occupational medicine, lung pediatricians, adult lung specialists), and thanks to close collaborations established with physicists, chemists, and physico-chemists (CNRS, CEA, Tokyo University, …). Our work is supported by grants from ANR,  Programme d’investissement d’avenir (LabEx SERENADE – https://serenade.cerege.fr, EquipEx NanoID – http://nano-id.fr/), ANSES, Chancellerie des Universités, Centre de compétence en Nanosciences d’île de France (C’Nano), Société de pneumologie de langue française (SPLF), …

 

Key words: lung, COPD, cigarette smoke, senescence, lung remodeling, carbon nanotubes, metal nanoparticles.

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Selected publications

Audureau E, Simon-Deckers A, Franco-Montoya ML, Annagi B, Kermanizadeh A, Boczkowski J, Lanone S. Substantial modification of the gene expression profile following exposure of macrophages to welding-related nanoparticles.

Sci. Rep. 04 june 2018, 8, art 8554

Cohignac V, Landry M, Ridoux A, Pinault M, Annangi B, Gerdil A, Herlin-Boime N, Mayne-L 'hermite M, Haruta M, Codogno P, Boczkowski J, Pairon JC, Lanone S. Carbon nanotubes but not spherical nanoparticles block autophagy process by a shape-related targeting of lysosomes in murine macrophages.

Autophagy. 2018 (in press).

Hadchouel A, Rousseau J, Rozé JC, Arnaud C, Bellino A, Couderc L, Marret S, Mittaine M, Pinquier D, Verstraete M, Ancel PY, Delacourt C; EPIPAGEADO study group. Association between asthma and lung function in adolescents born very preterm: results of the EPIPAGE cohort study.

Thorax. 2018 Mar 31.

Schlemmer F, Boyer L, Soumagne T, Ridoux A, Chouaid C, Maitre B, Lanone S, Adnot S, Audureau E, Boczkowski J. Beclin1 circulating levels and accelerated aging markers in COPD.

Cell Death Dis. 2018 Feb 5;9(2):156.

Andujar P, Courbon D, Bizard E, Marcos E, Adnot S, Boyer L, Demoly P, Jarvis D, Neukirch C, Pin I, Thabut G, Boczkowski J, Leynaert B. Smoking, telomere length and lung function decline: a longitudinal population-based study.

Thorax. 2018;73:283-285.

Paul E, Franco-Montoya ML, Paineau E, Angeletti B, Vibhushan S, Ridoux A, Tiendrebeogo A, Salome M, Hesse B, Vantelon D, Rose J, Canouï-Poitrine F, Boczkowski J, Lanone S, Delacourt C, Pairon JC. Pulmonary exposure to metallic nanomaterials during pregnancy irreversibly impairs lung development of the offspring.

Nanotoxicology. 2017;11(4):484-495.

Parpaleix A*, Boyer L*, Wiedemann A, Lacabaratz C, Margarit L, Enouf V, Le Corvoisier P, Lino A, Covali-Noroc A, Housset B, Chouaid C, Maitre B, Lévy Y, Lelièvre JD, Adnot S. Impaired humoral and cellular immune responses to influenza vaccination in chronic obstructive pulmonary disease patients.

J Allergy Clin Immunol. 2017;140:1754-1757.

Landry M, Pinault M, Tchankouo S, Charon É, Ridoux A, Boczkowski J, Mayne-L'Hermite M, Lanone S. Early signs of multi-walled carbon nanotbues degradation in macrophages, via an intracellular pH-dependent biological mechanism; importance of length and functionalization

Part Fibre Toxicol. 2016 Nov 24;13(1):61

Drummond D, Baravalle-Einaudi M, Lezmi G, Vibhushan S, Franco-Montoya ML, Hadchouel A, Boczkowski J, Delacourt C. Combined Effects of in Utero and Adolescent Tobacco Smoke Exposure on Lung Function in C57Bl/6J Mice

Environ Health Perspect. 2016 Nov 4

Présumé M, Simon-Deckers A, Tomkiewicz-Raulet C, Le Grand B, Tran Van Nhieu J, Beaune G, Duruphty O, Doucet J, Coumoul X, Pairon JC, Boczkowski J, Lanone S, Andujar P. Exposure to metal oxide nanoparticles administered at occupationally relevant doses induces pulmonary effects in mice

Nanotoxicology. 2016 Dec;10(10):1535-1544