Background: Cigarette smoking (CS) is a major risk factor for cardiovascular disease (CVD) through chronic inflammation. While its pulmonary effects are well established, the mechanisms linking lung inflammation to vascular injury remain unclear. Because neutrophils are early responders to CS-induced inflammation, we hypothesized that they drive systemic myelopoiesis and vascular inflammation via alarmin release. Methods: Wild-type (WT) mice were exposed to inhaled CS or orally administered cigarette smoke extract (CSE). Immune cell composition in lung, bronchoalveolar lavage fluid (BALF), blood, spleen, and bone marrow (BM) was assessed by flow cytometry. Hematopoietic stem and progenitor cell (HSPC) proliferation, reactive oxygen species (ROS) production, and S100A8/A9 release were quantified. Atherosclerosis progression was evaluated in Ldlr-/- mice fed a Western diet and treated with CSE. To define the role of neutrophil-derived S100A8/A9, bone marrow transplantation was performed using S100a9?/? or WT donors. Results: CS exposure increased circulating monocytes and neutrophils through enhanced BM myelopoiesis and elevated ROS-dependent S100A8/A9 release. Oral CSE reproduced these effects, indicating direct activation of neutrophils independent of pulmonary inflammation or lipid changes. In Ldlr-/- mice, CSE accelerated atherosclerosis by promoting infiltration of inflammasome-primed neutrophils, increased IL-1? release, and impaired macrophage efferocytosis. Hematopoietic S100a9 deletion normalized myelopoiesis and reduced vascular inflammation and plaque burden. Conclusions: Ingested CS components directly activate neutrophils to release S100A8/A9, triggering myelopoiesis and vascular inflammation. These findings reveal that tobacco's cardiovascular toxicity extends beyond inhalation, implicating oral exposure as a driver of systemic inflammation and atherogenesis.
Nagareddy et al. (2025) studied this question.