Title: Pulmonary effects of inhaled diesel exhaust in young and old mice: a pilot project.

Authors: Laskin, Debra L; Mainelis, Gediminas; Turpin, Barbara J; Patel, Kinal J; Sunil, Vasanthi R; HEI Health Review Committee

Published In Res Rep Health Eff Inst, (2010 Sep)

Abstract: It is well established that exposure to ambient fine particulate matter (PM), defined as PM < or = 2.5 microm in aerodynamic diameter (PM2.5), is associated with increased cardiovascular morbidity and mortality and that elderly persons are particularly susceptible to these effects. We speculated that the increased susceptibility of elderly persons to PM is due to altered production of inflammatory mediators and antioxidants in the lung. We performed pilot studies in an animal model to test this hypothesis. For these studies we used diesel exhaust (DE), a major component of urban PM, as a model. Two groups of male CB6F1 mice, 2 months and 18 months old, (referred to in this report as young and old mice, respectively) were exposed to DE at 300 or 1000 microg/m3 PM (referred to as low- or high-dose DE, respectively), or to filtered air as a control, for one 3-hour period (single exposure) or for 3 hours on each of three consecutive days (repeated exposure). Mice were killed and bronchoalveolar lavage (BAL) fluid, serum, and lung tissue were collected immediately after exposure (0 hours) and 24 hours after the final exposure. After single or repeated exposure to DE, persistent structural alterations and inflammation were observed in the lungs of old mice. These changes consisted of patchy thickening of alveolar septa and an increase in the number of neutrophils and macrophages in alveolar spaces. In the young mice, in contrast, no major alterations in lung histology were noted. In old but not in young mice, significant increases in messenger RNA (mRNA) expression of the oxidative-stress marker lipocalin 24p3 were also observed. In both young and old mice, exposure to DE was associated with increased expression of tumor necrosis factor alpha (TNF-alpha) mRNA in the lung. However, this response was attenuated in old mice. Exposure to high-dose DE resulted in significant increases in interleukin (IL)-6 and IL-8 mRNA expression in the lungs of old animals; these increases persisted for 24 hours. Whereas IL-6 was also up-regulated in young mice after DE exposure, no major effects were evident on the expression of IL-8 mRNA. Expression of the antioxidant enzyme manganese superoxide dismutase (MnSOD) was decreased in lung tissue from young animals after single or repeated exposure to DE. In contrast, constitutive expression of MnSOD was not evident in lungs of old mice, and DE had no effect on the expression of this antioxidant. These preliminary data confirm that old mice are more sensitive to DE than young mice and that increased sensitivity is associated with altered expression of inflammatory cytokines and the antioxidant MnSOD. These aberrations may contribute to the increased susceptibility of old mice to inhaled PM.

PubMed ID: 21381634

MeSH Terms: Administration, Inhalation; Age Factors; Animals; Biomarkers/analysis; Bronchoalveolar Lavage Fluid/cytology; Disease Models, Animal; Dose-Response Relationship, Drug; Immunohistochemistry; Inflammation Mediators/metabolism; Lung Diseases/chemically induced*; Lung Diseases/metabolism; Lung Diseases/pathology; Lung/drug effects*; Lung/metabolism; Lung/pathology; Male; Mice; Neutrophils; Particle Size; Particulate Matter/analysis; Particulate Matter/toxicity*; Pilot Projects; Reverse Transcriptase Polymerase Chain Reaction; Tumor Necrosis Factor-alpha/metabolism; Vehicle Emissions/analysis; Vehicle Emissions/toxicity*