TY - JOUR T1 - Muscarinic M<sub>3</sub> receptors on structural cells regulate neutrophilic inflammation in mice JF - European Respiratory Journal JO - Eur Respir J VL - 44 IS - Suppl 58 SP - P869 AU - Loes Kistemaker AU - Ronald Van Os AU - Bertien Ausema AU - Sophie Bos AU - Machteld Hylkema AU - Pieter Hiemstra AU - Jurgen Wess AU - Herman Meurs AU - Huib Kerstjens AU - Reinoud Gosens Y1 - 2014/09/01 UR - http://erj.ersjournals.com/content/44/Suppl_58/P869.abstract N2 - IntroductionAnticholinergics, which block the M3 receptor, are effective bronchodilators for patients with COPD. Recent evidence from M3 receptor deficient mice (M3R-/-) indicates that M3 receptors also regulate neutrophilic inflammation in response to cigarette smoke (CS). M3 receptors are present on almost all cell types and in this study we investigated the relative contribution of the M3 receptor on structural cells versus hematopoietic cells to CS-induced inflammation using chimeric mice.MethodsChimeric animals were generated and after 10 weeks engraftment was analyzed by flow-cytometry. Thereafter, irradiated and non-irradiated control animals were exposed to CS or fresh air for four consecutive days.ResultsEngraftment was high and not different between the groups. CS exposure induced a small, nonsignificant increase in macrophage numbers in BALF in all groups (1.3-1.4 fold). No increase in lymphocyte numbers was observed. CS induced a significant increase in neutrophil numbers in non-irradiated and irradiated control animals (4-35 fold). Interestingly, WT animals receiving M3-/- bone marrow showed a similar increase in neutrophil number (15-fold). In contrast, no increase in the number of neutrophils was observed in M3R-/- animals receiving WT bone marrow. The increase in KC levels was similar in all smoke-exposed groups, both on mRNA (2.8-5.0 fold) and protein level (2.5-9.6 fold). No increase in IL-6 expression was observed.ConclusionsThese findings suggest that the M3 receptor on structural cells plays a pro-inflammatory role in CS-induced neutrophilic inflammation, whereas the M3 receptor on hematopoietic cells does not. This effect is probably not mediated via IL-6 or IL-8 release. ER -