title: Impaired resolution of inflammatory response in the lungs of JF1/Msf mice following carbon nanoparticle instillation.
abstract: BACKGROUND
  Declined lung function is a risk factor for particulate matter associated respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD). Carbon nanoparticles (CNP) are a prominent component of outdoor air pollution that causes pulmonary toxicity mainly through inflammation. Recently we demonstrated that mice (C3H/HeJ) with higher than normal pulmonary function resolved the elicited pulmonary inflammation following CNP exposure through activation of defense and homeostasis maintenance pathways. To test whether CNP-induced inflammation is affected by declined lung function, we exposed JF1/Msf (JF1) mice with lower than normal pulmonary function to CNP and studied the pulmonary inflammation and its resolution.
  
  
  METHODS
  5 μg, 20 μg and 50 μg CNP (Printex 90) were intratracheally instilled in JF1 mice to determine the dose response and the time course of inflammation over 7 days (20 μg dosage). Inflammation was assessed using histology, bronchoalveolar lavage (BAL) analysis and by a panel of 62 protein markers.
  
  
  RESULTS
  24 h after instillation, 20 μg and 50 μg CNP caused a 25 fold and 19 fold increased polymorphonuclear leucocytes (PMN) respectively while the 5 μg represented the 'no observable adverse effect level' as reflected by PMN influx (9.7 × 10E3 vs 8.9 × 10E3), and BAL/lung concentrations of pro-inflammatory cytokines. Time course assessment of the inflammatory response revealed that compared to day1 the elevated BAL PMN counts (246.4 × 10E3) were significantly decreased at day 3 (72.9 × 10E3) and day 7 (48.5 × 10E3) but did not reach baseline levels indicating slow PMN resolution kinetics. Strikingly on day 7 the number of macrophages doubled (455.0 × 10E3 vs 204.7 × 10E3) and lymphocytes were 7-fold induced (80.6 × 10E3 vs 11.2 × 10E3) compared to day1. At day 7 elevated levels of IL1B, TNF, IL4, MDC/CCL22, FVII, and vWF were detected in JF1 lungs which can be associated to macrophage and lymphocyte activation.
  
  
  CONCLUSIONS
  This explorative study indicates that JF1 mice with impaired pulmonary function also exhibits delayed resolution of particle mediated lung inflammation as evident from elevated PMN and accumulation of macrophages and lymphocytes on day 7. It is plausible that elevated levels of IL1B, IL4, TNF, CCL22/MDC, FVII and vWF counteract defense and homeostatic pathways thereby driving this phenomenon.
authors.affiliation: Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg/Munich, Germany.
authors.forename: Koustav
authors.initials: K
authors.lastname: Ganguly
authors.forename: Swapna
authors.initials: S
authors.lastname: Upadhyay
authors.forename: Martin
authors.initials: M
authors.lastname: Irmler
authors.forename: Shinji
authors.initials: S
authors.lastname: Takenaka
authors.forename: Katrin
authors.initials: K
authors.lastname: Pukelsheim
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.forename: Martin Hrabé
authors.initials: MH
authors.lastname: De Angelis
authors.forename: Eckard
authors.initials: E
authors.lastname: Hamelmann
authors.forename: Tobias
authors.initials: T
authors.lastname: Stoeger
authors.forename: Holger
authors.initials: H
authors.lastname: Schulz
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002244:Carbon; D004195:Disease Models, Animal; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D008214:Lymphocytes / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D053758:Nanoparticles; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D011506:Proteins / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D013997:Time Factors
chemical_list: D018836:Inflammation Mediators; D011506:Proteins; D002244:Carbon