Smoking-induced Reprogramming of Histamine Metabolism Genes in the Human Small Airway Epithelium

Smoking is associated with increased airway histamine responsiveness and elevated histamine levels. Transcript levels of histidine decarboxylase (HDC; histamine synthesis) and histamine N-methyltransferase (HNMT; histamine degradation) were evaluated in small airway epithelial (SAE) cells obtained from smokers or non-smokers. Histamine+ SAE cells increased in smokers compared to nonsmokers (p< 0.03). HDC transcript levels were elevated in smokers compared with non-smokers when comparing both bulk RNA from SAE (p< 0.03) and single cell HDC transcripts in mast cells (p<10-6). Elevated HDC transcript levels in mast cells corre-lated with elevated IL33 transcript levels in smoker SAE basal cells, and elevated transcript levels of the IL33 receptor, IL1RL1, in mast cells. In contrast to HDC, transcript levels of HNMT were decreased (p<10-4) in smoker SAE. Significant decreases in HNMT transcript levels were found broadly across SAE differentiated cell types. An in vitro SAE culture model treated with cigarette smoke extract reduced HNMT transcript levels (p<0.05). Together, the data suggests that smoking results in an accumulation of mast cells, elevated expression of histamine-synthesizing mast cell HDC, and a decrease in histamine-degrading HNMT transcript levels broadly in the epithelium. These smoking induced changes are likely contributors to elevated histamine levels in the airways of smokers. Analysis of bulk RNA-Seq samples obtained from n=20 healthy nonsmokers and n=24 healthy smokers were used for quantification of histamine+ cells. Single cell-RNAseq identified SAE cell-type specific deregulation of histamine metabolism genes by smoking.