The Effects of Smoking on the Lipopolysaccharide Response and Glucocorticoid Sensitivity of Alveolar Macrophages of Patients With Asthma

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Abstract

Background Cigarette smoking in asthma causes insensitivity to inhaled glucocorticoids (GCs). We tested the hypothesis that smoking causes GC insensitivity in alveolar macrophages (AMs) from asthmatics. Methods 19 asthmatic nonsmokers (ANS) and 13 asthmatic smokers (AS) underwent BAL. AMs were cultured with or without dexamethasone 0.1-1000nM for 2 h before LPS (1ug/mL) stimulation. After 6 h, supernatants were harvested for ELISA, and messenger RNA collected for real-time (RT)-PCR. Results AS had higher numbers of AMs per mL of BAL than ANS (1.98 vs 0.75 x 10(6), p = 0.007). Cigarette smoking significantly attenuated the LPS response for all three cytokines tested [ANS vs AS; TNFalpha 31.6 vs 10.6ng/mL (p = 0.01), IL-6 25.8 vs 10.8ng/mL (p = 0.002) and IL-8 62.5 vs 36.1ng/mL (p = 0.001) respectively]. There was no difference in dexamethasone dose response curves between ANS and AS (p > 0.05 all comparisons). IC(50) was; IL-6 120.6 vs 83.3 and TNFalpha 4.9 vs 8.6 respectively, 50 inhibition of IL-8 was not achieved. RT-PCR also showed no difference in the suppression of cytokine messenger RNA levels between groups, with IL-8 being the most GC insensitive cytokine. Conclusion Cigarette smoking in asthmatics increases the number of airway AMs and attenuates their response to LPS which may have implications in host immune function. Cigarette smoking does not alter the GC sensitivity of AMs in asthmatics. There was differential cytokine sensitivity with IL-8 being the least GC sensitive cytokine. GC insensitive IL-8 production from AMs may be a mechanism by which neutrophils are attracted into the airways.

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