For decades, smoking's cardiovascular harm has been attributed largely to lung inflammation spilling over into systemic circulation — but a precise molecular chain of events has remained elusive. New mechanistic evidence now identifies a specific immune pathway that may explain why smokers develop accelerated arterial plaque, offering a targetable mechanism independent of pulmonary damage and potentially relevant to nicotine product users broadly.
Using both inhalation and oral cigarette smoke extract models in mice, researchers traced a cascade beginning at the bone marrow: smoke exposure amplifies myelopoiesis — the production of immune cells — elevating circulating monocytes and neutrophils. These activated neutrophils release S100A8/A9 proteins, calcium-binding alarmins that signal systemic inflammation. Crucially, oral smoke extract reproduced the same effects as inhaled exposure, demonstrating that neutrophil activation occurs through direct chemical stimulation rather than secondarily through lung injury. In LDL receptor-deficient mice fed a Western diet, smoke extract measurably accelerated atherosclerotic plaque progression. Bone marrow transplantation experiments using S100a9-knockout donors confirmed that neutrophil-derived S100A8/A9 is causally required for this vascular aggravation.
S100A8/A9 — also called calprotectin — has emerged over the past decade as a key danger signal linking innate immune activation to cardiometabolic disease, with elevated plasma levels already associated with coronary events in human cohorts. What makes this work analytically significant is the demonstration of a gut-to-bone-marrow-to-artery axis that bypasses pulmonary inflammation entirely, which challenges the assumption that respiratory harm is the primary mediator of smoking's cardiovascular toxicity. The limitation is that all data are murine, and human validation is needed before clinical translation. Still, this finding is potentially paradigm-shifting: it suggests that anti-S100A8/A9 strategies or neutrophil-targeted interventions — already under investigation for other inflammatory conditions — deserve evaluation as cardiovascular risk modifiers in smokers.