Nicotinic acetylcholine receptor variants associated with susceptibility to chronic obstructive pulmonary disease: a meta-analysis

<p>Abstract</p> <p>Background</p> <p>Only 10-15% of smokers develop chronic obstructive pulmonary disease (COPD) which indicates genetic susceptibility to the disease. Recent studies suggested an association between COPD and polymorphisms in <it>CHRNA </it>coding subunits of nicotinic acetylcholine receptor. Herein, we performed a meta-analysis to clarify the impact of <it>CHRNA </it>variants on COPD.</p> <p>Methods</p> <p>We searched Web of Knowledge and Medline from 1990 through June 2011 for COPD gene studies reporting variants on <it>CHRNA</it>. Pooled odds ratios (ORs) were calculated using the major allele or genotype as reference group.</p> <p>Results</p> <p>Among seven reported variants in <it>CHRNA</it>, rs1051730 was finally analyzed with sufficient studies. Totally 3460 COPD and 11437 controls from 7 individual studies were pooled-analyzed. A-allele of rs1051730 was associated with an increased risk of COPD regardless of smoking exposure (pooled OR = 1.26, 95% CI 1.18-1.34, p < 10^-5). At the genotypic level, the ORs gradually increased per A-allele (OR = 1.27 and 1.50 for GA and AA respectively, p < 10^-5). Besides, AA genotype exhibited an association with reduced FEV1% predicted (mean difference 3.51%, 95%CI 0.87-6.16%, p = 0.009) and increased risk of emphysema (OR 1.93, 95%CI 1.29-2.90, p = 0.001).</p> <p>Conclusions</p> <p>Our findings suggest that rs1051730 in <it>CHRNA </it>is a susceptibility variant for COPD, in terms of both airway obstruction and parenchyma destruction.</p

The epithelial cholinergic system of the airways

Acetylcholine (ACh), a classical transmitter of parasympathetic nerve fibres in the airways, is also synthesized by a large number of non-neuronal cells, including airway surface epithelial cells. Strongest expression of cholinergic traits is observed in neuroendocrine and brush cells but other epithelial cell types—ciliated, basal and secretory—are cholinergic as well. There is cell type-specific expression of the molecular pathways of ACh release, including both the vesicular storage and exocytotic release known from neurons, and transmembrane release from the cytosol via organic cation transporters. The subcellular distribution of the ACh release machineries suggests luminal release from ciliated and secretory cells, and basolateral release from neuroendocrine cells. The scenario as known so far strongly suggests a local auto-/paracrine role of epithelial ACh in regulating various aspects on the innate mucosal defence mechanisms, including mucociliary clearance, regulation of macrophage function and modulation of sensory nerve fibre activity. The proliferative effects of ACh gain importance in recently identified ACh receptor disorders conferring susceptibility to lung cancer. The cell type-specific molecular diversity of the epithelial ACh synthesis and release machinery implies that it is differently regulated than neuronal ACh release and can be specifically targeted by appropriate drugs

Nicotine exerts an anti-inflammatory effect in a murine model of acute lung injury

Activation of the cholinergic anti-inflammatory pathway through direct activation of nicotinic acetylcholine receptors on immune cells can inhibit pro-inflammatory chemokine and cytokine release and thereby protect in a variety of inflammatory diseases. The aim of this study was to investigate whether nicotine treatment protected against acute lung inflammation. Mice challenged with intratracheal lipopolysaccharide (LPS, 50 μg) were treated with nicotine (0.2 or 0.4 mg/kg, sc). After 24 h, bronchoalveolar lavage fluid (BALF) was obtained to measure leukocyte infiltration, lung edema, and pro-inflammatory chemokine (MIP-1α, MIP-2, and eotaxin) and cytokine (IL-1, IL-6, and TNF-α) levels. Nicotine treatment reduced the LPS-mediated infiltration of leukocytes and edema as evidenced by decreased BALF inflammatory cells, myeloperoxidase, and protein. Nicotine also downregulated lung production of pro-inflammatory chemokines and cytokines. These data support the proposal that activation of the cholinergic anti-inflammatory pathway may represent a useful addition to the therapy of acute respiratory distress syndrome

Activation of the Cholinergic Antiinflammatory Pathway Reduces Ricin-Induced Mortality and Organ Failure in Mice

Exposure to ricin, either by accident through ingestion of castor oil plant seeds or intentionally through its use as a bioweapon, invariably leads to multiple organ damage and death. Currently there is only a vaccine in advanced development to ricin, but no other antidote. Ricin causes systemic inflammation with increased proinflammatory cytokine release and subsequent multiple organ failure, particularly kidney and liver dysfunction. Activation of the cholinergic antiinflammatory pathway, specifically through the alpha7 nicotinic acetylcholine receptor (either indirectly through vagus nerve stimulation or directly through nicotine treatment) reduces proinflammatory gene expression. This activation also increases release of proinflammatory chemokines and cytokines, and has proven effective in a variety of inflammatory diseases. The aim of this study was to investigate whether nicotine treatment protected against ricin toxicity in mice. Male Balb/c mice exposed to ricin had increased serum levels of the inflammatory cytokine tumor necrosis factor-α and markers of both kidney (blood urea nitrogen, creatine) and liver (alanine tranaminase) dysfunction, with a subsequent increase in mortality. Nicotine administration 2 h after ricin injection significantly delayed and reduced ricin-induced mortality, an effect coupled with reduced serum levels of tumor necrosis factor-α and markers of kidney and liver dysfunction. Both the kidney and liver had markedly increased cellular oxidative stress following ricin exposure, an effect attenuated by nicotine administration. In conclusion, these data demonstrate that in cases of ricin poisoning, activation of the cholinergic antiinflammatory pathway may prove beneficial by reducing organ damage, delaying mortality, and allowing for a greater chance of survival