Exposure to the heated tobacco product IQOS generates apoptosis-mediated pulmonary emphysema in murine lungs

Pulmonary emphysema is predominantly caused by chronic exposure to cigarette smoke (CS). Novel tobacco substitutes, such as heated tobacco products (HTPs), have emerged as healthier alternatives to cigarettes. 100S, the most popular HTP in Japan, is advertised as harmless compared with conventional cigarettes. Although some studies have reported its toxicity, few in vivo studies have been conducted. Here, 12-wk-old C57BL6/J male mice were divided into three groups and exposed to air (as control), 100S aerosol, or CS for 6 mo. After exposure, the weight gain was significantly suppressed in the IQOS and CS groups compared with the control ( 4.93 g; IQOS vs. air and 5.504 g; CS vs. air). The serum cotinine level was significantly higher in the 100S group than in the control group. The neutrophils and lymphocyte count increased in the bronchoalveolar lavage fluid of the IQOS and CS groups compared with those in the control group. Chronic IQOS exposure induced pulmonary emphysema similar to that observed in the CS group. Furthermore, expression levels of the genes involved in the apoptosis-related pathways were significantly upregulated in the lungs of the IQOS-exposed mice. Cytochrome c, cleaved caspase-3, and cleaved poly (ADP-ribose) polymerase-1 were overexpressed in the IQOS group compared with the control. Single-stranded DNA and TdT-mediated dUTP nick-end labeling-positive alveolar septal cell count significantly increased in the 100S group compared with the control. In conclusion, chronic exposure to IQOS aerosol induces pulmonary emphysema predominantly via apoptosis-related pathways. This suggests that HTPs are not completely safe tobacco products.