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

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 (α7^G) and those in which the α7-receptor signaling mechanisms are restricted by point mutation (α7^E260A:G). Flow cytometry results show that after CS there is an increase in a subset of CD11c (CD11c^hi) alveolar macrophages (AMs) and histology reveals an increase in these cells within the alveolar space in both genotypes although the α7^E260A:G AMs tend to accumulate into large aggregates rather than more widely distributed solitary cells common to the α7^G 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 α7^E260A: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 α7^G 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. [ABSTRACT FROM AUTHOR]