Lung epithelial response to cigarette smoke and modulation by the nicotinic alpha 7 receptor

Abstract

Cigarette smoking (CS) is a principal contributor to a spectrum of devastating lung diseases whose occurrence and severity may vary between individuals and not appear for decades after prolonged use. One explanation for the variability and delay in disease onset is that nicotine, the addictive component of CS, acts through the ionotropic nicotinic acetylcholine receptor (nAChR) alpha7 (α7) to modulate anti-inflammatory protection. In this study we measured the impact α7 signaling has on the mouse distal lung response to side-stream CS exposure for mice of the control genotype (α7G) and those in which the α7-receptor signaling mechanisms are restricted by point mutation (α7E260A:G). Flow cytometry results show that after CS there is an increase in a subset of CD11c (CD11chi) alveolar macrophages (AMs) and histology reveals an increase in these cells within the alveolar space in both genotypes although the α7E260A:G AMs tend to accumulate into large aggregates rather than more widely distributed solitary cells common to the α7G lung after CS. Changes to lung morphology with CS in both genotypes included increased tissue cavitation due to alveolar expansion and bronchial epithelium dysplasia in part associated with altered club cell morphology. RNA-Seq analysis revealed changes in epithelium gene expression after CS are largely independent of the α7-genotype. However, the α7E260A:G genotype did reveal some unique variations to transcript expression of gene sets associated with immune responsiveness and macrophage recruitment, hypoxia, genes encoding mitochondrial respiration complex I and extracellular fibrillary matrix proteins (including alterations to fibrotic deposits in the α7G proximal airway bronchioles after CS). These results suggest α7 has a central role in modulating the response to chronic CS that could include altering susceptibility to associated lung diseases including fibrosis and cancer.

Total flavonoids from sea buckthorn ameliorates lipopolysaccharide/cigarette smoke‐induced airway inflammation

“…LPS, the major component of the outer membrane of Gram‐negative bacteria, is a potent toll‐like receptor 4 (TLR4) agonist that can activate various immune cells in the respiratory tract, including bronchial epithelial cells and alveolar macrophages (Man, de Steenhuijsen Piters, & Bogaert, ). CS also can directly attack these respiratory tract cells through activation of TLR4 or α7 nicotinic acetylcholine receptor (Gahring, Myers, Dunn, Weiss, & Rogers, ; Maouche et al, ). However, single intraperitoneal injection of LPS (10–15 mg/kg) always causes severe acute lung injury and higher mortality (Du et al, ; Tsoyi et al, ), which are very different from chronic airway inflammation, such as chronic bronchitis and chronic obstructive pulmonary disease.…”

Age-Associated Tooth Loss and Oral Microbial Dysbiosis in a Mouse Genetic Model of Chronic Nicotine Exposure

“…One approach to defining the role of α7 in these processes has been through the application of genetic manipulation of individual nAChR subunits to impact receptor function in specific ways. In this case the α7 E260A:G mouse has been implemented to specifically define how signaling through the α7 ion channel couples to cell signaling events with consequence on a broad range of immune responses to allergens and bacterial agents (10)(11)(12)(13)26) and developmental process including tooth and enamel development (8). This mouse has the added advantage over genetic ablation due the minimally invasive nature of the missense mutation to the gene and genomic structure and complications that arise due to abnormal receptor expression or even compensation.…”

“…It is also expressed by autonomic neurons, keratinocytes, immune cells (particularly macrophages), endothelium, epithelial cells and even highly specialized cells such as ameloblasts (3,(7)(8)(9)(10). However, how the nicotine-α7 interaction modulates peripheral cellular responses and especially in the immune system in response to inflammatory processes is not straightforward and mechanistically distinct from CS (10)(11)(12)(13). First, the α7 receptor couples to signaling mechanisms in part through its large receptor calcium current that, in addition to the normal sodium/potassium currents, is sufficient to modulate intracellular signaling cascades and transcriptional networks (3,14).…”

Kynurenic acid and cancer: facts and controversies

“…Although the antiangiogenic potential of KYNA, as an antagonist of alpha7 nAChR, in cancer cells has not been excessively studied, Arias et al [73] reviewed that selective (alpha-bungarotoxin and methyllycaconitine) and non-specific (mecamylamine) antagonists of this receptors inhibited proliferation of endothelial cells and angiogenesis. Importantly, alpha7 nAChR is also involved in the modulation of anti-inflammatory response [75], Fig. 3 A schematic presentation of selected cellular processes influenced by KYNA.…”