Effect of Inhaled Endotoxin on Mucociliary Clearance and Airway Inflammation in Mild Smokers and Nonsmokers

Abstract

Background: In healthy nonsmokers, inhaled endotoxin [lipopolysaccharide (LPS)] challenge induces airway neutrophilia and modifies innate immune responses, but the effect on mucociliary clearance (MCC), a key host defense response, is unknown. Although smokers are chronically exposed to LPS through inhaled tobacco smoke, the acute effect of inhaled LPS on both MCC and airway inflammation is also unknown. The purpose of this study was to determine the effect of inhaled LPS on MCC in nonsmokers and mild smokers with normal pulmonary function. Methods:We performed an open-label inhalational challenge with 20,000 endotoxin units in healthy adult nonsmokers (n¼18) and young adult, mild smokers (n¼12). At 4 hr post LPS challenge, we measured MCC over a period of 2 hr, followed by sputum induction to assess markers of airway inflammation. Results: No significant changes in spirometry occurred in either group following LPS challenge. Following LPS, MCC was significantly ( p < 0.05) slowed in nonsmokers, but not in smokers [MCC¼10 -9% (challenge) vs. 15 -8% (baseline), MCC¼14 -9% (challenge) vs. 16 -10% (baseline), respectively]. Both groups showed a significant ( p < 0.05) increase in sputum neutrophils 6 hr post LPS challenge versus baseline. Although there was no correlation between the increased neutrophilia and depressed MCC post LPS in the nonsmokers, baseline neutrophil concentration predicted the LPS-induced decrease in MCC in the nonsmokers, i.e., lower baseline neutrophil concentration was associated with greater depression in MCC with LPS challenge ( p < 0.05). Conclusions: These data show that a mild exposure to endotoxin acutely slows MCC in healthy nonsmokers. MCC in mild smokers is unaffected by mild endotoxin challenge, likely due to preexisting effects of cigarette smoke on their airway epithelium.

Gamma tocopherol-enriched supplement reduces sputum eosinophilia and endotoxin-induced sputum neutrophilia in volunteers with asthma

“…We observed a significant impairment of MCC following inhaled LPS challenge during the placebo treatment period but not during the γT treatment period. We have previously found a slowing of MCC by LPS challenge in healthy non-smokers (35) and a trend towards slowing in mild asthmatics that was confounded by regional deposition differences between baseline and post-LPS challenge MCC (unreported) (38). While this study was not powered to detect a significant treatment effect of γT on MCC, our results do suggest that γT reduces LPS-induced slowing of MCC, and warrants further study.…”

“…The procedure used for measuring MCC in humans has been described in detail previously (35, 36). Briefly, volunteers inhaled an aerosol of 99m Tc-sulfur colloid ( 99m Tc -SC) using a slow inhalation (80 mL/sec), large particle (9.5 μm mass median aerodynamic diameter) method (37).…”

“…A whole lung region of interest bordering the right lung (created from a Co57 transmission lung scan (37)) was used to determine, by computer analysis, the whole lung retention (Rt) (decay and background corrected) as a fraction of the initial counts in the right lung, over the two-hour clearance period at 10-minute intervals. MCC was calculated and expressed as average clearance in percent over the two-hour period (35). Because measures of MCC can be influenced by the initial, regional lung deposition of the inhaled radioaerosol, we also calculated 1) the central to peripheral (C/P) ratio of activity and 2) the skew of the counts/pixel vs. number of pixels histogram for the initial two-minute image from each study visit (35, 38).…”

“…MCC was calculated and expressed as average clearance in percent over the two-hour period (35). Because measures of MCC can be influenced by the initial, regional lung deposition of the inhaled radioaerosol, we also calculated 1) the central to peripheral (C/P) ratio of activity and 2) the skew of the counts/pixel vs. number of pixels histogram for the initial two-minute image from each study visit (35, 38).…”