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Effects of a combination of subchronic tobacco smoke exposure and lipopolysaccharide administration on pulmonary inflammation in the mouse

Freeman, Mark and Hardaker, Liz and Banner, Kathy and Poll, Christopher and Coulthard, Alex and Dewhurst, Jennifer (2011) Effects of a combination of subchronic tobacco smoke exposure and lipopolysaccharide administration on pulmonary inflammation in the mouse. British Journal of Pharmacology, 8 (1). 132P.

Abstract

Chronic Obstructive Pulmonary Disease (COPD) is characterised by a predominantly irreversible restriction of airflow and often by acute exacerbations (AECOPD). These exacerbations are defined as a worsening of symptoms that result in a need to alter medication and are associated with an altered inflammatory response and a decline in lung function. Tobacco smoking is widely accepted as the main causative agent for COPD, with the majority of exacerbations being associated with subsequent bacterial or viral infection. Our aim was to develop a model that would mimic aspects of the altered inflammatory response observed in a bacteria-induced AECOPD. We combined multiple wholebody tobacco smoke (TS) exposures with the administration of the bacterial mimetic lipopolysaccharide (LPS). Each week for the first five weeks, female Balb/c mice (n=8-10 per group) were exposed twice a day to 30 minutes of either TS (750µg/l wet total particulate matter) or room air (RA) on days 1-5. On days 6 and 7 they were rested. During week six, the protocol was the same for the first two days. On the morning of day three LPS (0.3mg/kg; E.coli 0111:B4) or saline (0.9%w/v) were administered intranasally under isoflurane anaesthesia followed 5 hours later by TS or RA exposure. Twenty four hours after LPS administration animals were terminally anaesthetised (Fentanyl citrate 0.8mg/kg, Fluanisone 25mg/kg and Midazolam 12.45mg/kg i.p.) and the trachea cannulated. Bronchoalveolar lavage (BAL) was then performed to assess cell influx (Table1), cytokine levels and cytotoxicity. Data are expressed as the mean ±SEM with n=8-10 animals per group. BAL total cells were elevated in mice exposed to the combination of LPS and TS compared to those exposed to TS alone. However, the increase in total cells, compared to RA/saline controls, was lower in the mice exposed to LPS/TS compared to those exposed to LPS alone (Table 1). Neutrophils showed a comparable profile. Interleukin-6 (IL-6) concentrations in the BAL were significantly elevated in the RA/LPS (1687±176pg/ml) animals compared to RA/Saline (57±9 pg/ml) mice. They were also significantly elevated in the TS/LPS animals (745±125 pg/ml) but to a lesser extent. Interleukin-1β and keratinocyte cytokine (KC) showed similar profiles. Lactate dehydrogenase (LDH) activity, a marker of cytotoxicity, was highest in the BAL of TS/LPS treated animals (1.9±0.3 absorbance units (AU)) compared with either the RA/LPS animals (1.3±0.2AU), the TS/Saline mice (0.9±0.1) or the RA/Saline mice (0.2±0). These data indicate that certain aspects of the inflammatory response to LPS are reduced after 6 weeks TS exposure. This animal model may be useful for investigating the altered inflammatory response observed during an AECOPD.
Table 1: Effect of LPS and tobacco smoke exposure on cell numbers in the BAL.
Treatment groups RA/Saline RA/LPS TS/Saline TS/LPS
Total cells 100 ± 14 1438 ±167(###) 477 ± 31 992 ± 166(###)
Neutrophils 2 ± 1 1253 ± 155(###) 267 ± 19 736 ± 128(###)
Macrophages 98 ± 14 183 ± 30 208 ± 23(#) 256 ± 47(##)
Data expressed as mean cells x 103/ml ± sem. (Kruskal-Wallis followed by Dunn’s post test was used # p<0.05, ## p<0.01, ### p<0.001 compared to RA/Saline control.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/3802

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