Toxicity of tobacco products and nicotine on neutrophil host defense: an in vivo and in vitro approach.

Although heated tobacco products (HTPs) reduce combustion-derived toxicants, increasing evidence indicates that they still induce adverse biological effects whose mechanisms remain poorly understood. We previously showed that HTP exposure impairs, whereas conventional cigarette (CC) exposure exacerbates, neutrophil influx into the inflamed synovium of mice with antigen-induced arthritis (AIA). Here, we investigated the effects of HTP vapor, CC smoke, and vaporized nicotine on neutrophil production and function. Naive and AIA mice and bone marrow (BM)-derived neutrophils were exposed to HTP vapor, CC smoke, or vaporized nicotine. Exposures were carried out in nicotine-equivalent model conditions. In vivo, CC exposure enhanced granulopoiesis, whereas HTP exposure impaired this process, as determined by the numbers of blast cells, immature neutrophils, and mature segmented neutrophils in the BM. In contrast, nicotine exposure increased the numbers of blast cells and band neutrophils and reduced mature circulating neutrophils; nonetheless, it did not alter neutrophil recruitment into the inflamed joint cavity. In BM-derived neutrophils, HTP vapor, CC smoke, and nicotine differentially affected neutrophil function. All exposures increased reactive oxygen species production. CC smoke increased ionomycin-induced extracellular DNA release, whereas both HTP vapor and CC smoke impaired chemotaxis. In contrast, nicotine enhanced neutrophil migratory capacity. STAT3 signaling was modulated following CC smoke and nicotine exposure but not HTP vapor. Together, these in vivo and in vitro findings demonstrate that CC smoke, HTP vapor, and nicotine differentially regulate neutrophil biology. Furthermore, these suggest that other constituents besides nicotine contribute substantially to HTP-induced immunotoxicity, providing mechanistic evidence that these products directly interfere with innate immune responses under inflammatory conditions.