Th1 cells directly respond to short-chain LPS. Cigarette smoking suppresses Th1-mediated immune responses to gram-negative bacterial infections by interfering with MyD88/IRAK signaling thereby reducing LPS-induced TLR4 expression. This can explain the increased susceptibility to bacterial infections in COPD. Targeting TLR signaling might be useful to reduce exacerbation rates.

No abstract

During bacterial infections, pathogen-associated molecular patterns (PAMPs) induce cytokine/chemokine release in immunoactive cells. This increases corticosteroid-resistant airway inflammation in chronic obstructive pulmonary disease (COPD) and leads to exacerbations. Anti-inflammatory therapies other than corticosteroids are required and resveratrol is currently under discussion. Resveratrol is an activator of sirtuins, which are class III histone deacetylases (HDACs). We suggested that human airway smooth muscle cells (HASMCs) release COPD-associated cytokines/chemokines in response to lipoteichoic acid (LTA), a major PAMP of gram-positive bacteria and that resveratrol is superior to the corticosteroid dexamethasone in suppressing these cytokines/chemokines. Cultivated HASMCs of patients with COPD were pre-incubated with resveratrol or dexamethasone before stimulation with LTA. CCL2, GM-CSF, IL-6 and IL-8 were analysed in culture supernatants by enzyme-linked immunosorbent assay. Drug effects were investigated in the absence and presence of trichostatin A (TSA), an inhibitor of class I/II HDACs, and EX527, an inhibitor of the sirtuin SIRT1. LTA induced robust cytokine/chemokine release. Resveratrol was superior to dexamethasone in reducing CCL-2, IL-6 and IL-8 in LTA-exposed HASMCs of patients with COPD. Both drugs were equally effective in reducing GM-CSF. Resveratrol effects were partially reversed by EX527 but not by TSA. Dexamethasone effects were partially reversed by TSA but not by EX527. We conclude that HASMCs contribute to the increase in airway inflammation in COPD exacerbations caused by gram-positive bacterial infections. Our data suggest resveratrol as an alternative anti-inflammatory therapy in infection-induced COPD exacerbations. Resveratrol and corticosteroids suppress cytokine/chemokine expression through activation of SIRT1 or interaction with class I/II HDACs, respectively, in HASMCs.

Airway inflammation in chronic obstructive pulmonary disease (COPD) is believed to be insensitive to corticosteroids. However, corticosteroids are recommended in COPD (GOLD stages III, IV) with frequent exacerbations. Resveratrol has anti-inflammatory properties and could be an alternative to corticosteroids in COPD therapy. We investigated the effect of dexamethasone versus resveratrol on the release of COPD-related inflammatory mediators (IL-6, IL-8, GM-CSF and MCP-1) and matrix-metalloprotease-9 (MMP-9) from alveolar macrophages exposed to gram-negative bacterial endotoxin (lipopolysaccharide, LPS). We compared never-smokers, current smokers without airway obstruction and current smokers with COPD. The cytokines and MMP-9 were measured in cell culture supernatants with ELISA. The release of IL-8 and MMP-9 from LPS-exposed alveolar macrophages was increased in COPD, the release of GM-CSF and IL-6 was decreased in COPD and the release of MCP-1 was without differences between the cohorts. Dexamethasone impaired the release of all cytokines and MMP-9 from LPS-exposed alveolar macrophages of all cohorts, but for IL-8 and GM-CSF this effect was reduced in COPD. In alveolar macrophages of COPD, there was an almost complete reduction in IL-6 release but only a partial reduction in IL-8, GM-CSF, MCP-1 and MMP-9 release demonstrating a partial corticosteroid-insensitivity. In contrast, resveratrol almost completely reduced the release of all cytokines and MMP-9 without significant differences between the cohorts. Our data provide evidence for a corticosteroid resistance of alveolar macrophage-dependent inflammatory responses induced by gram-negative bacteria in COPD and thus question the utility of corticosteroids in COPD therapy. Instead, resveratrol may prove an alternative.