Nitin Kumar

BACKGROUND: Cigarette smoking (CS) is a major risk factor for cardiovascular disease 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 mice were exposed to inhaled CS or orally administered cigarette smoke extract. Immune cell composition in lung, bronchoalveolar lavage fluid, blood, spleen, and bone marrow was assessed by flow cytometry. Hematopoietic stem and progenitor cell proliferation, reactive oxygen species production, and S100A8/A9 (S100 calcium-binding protein A8/A9) release were quantified. Atherosclerosis progression was evaluated in Ldlr ^−/− (low-density lipoprotein receptor-deficient) mice fed a Western diet and treated with cigarette smoke extract. To define the role of neutrophil-derived S100A8/A9, bone marrow transplantation was performed using S100a9 ^−/− or wild-type donors. RESULTS: CS exposure increased circulating monocytes and neutrophils through enhanced bone marrow myelopoiesis and elevated reactive oxygen species-dependent S100A8/A9 release. Oral cigarette smoke extract reproduced these effects, indicating direct activation of neutrophils independent of pulmonary inflammation or lipid changes. In Ldlr ^−/− mice, cigarette smoke extract accelerated atherosclerosis by promoting infiltration of inflammasome-primed neutrophils, increasing IL-1β (interleukin 1 beta) release, and impairing 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.

Meta-analysis of transcripts in colon adenocarcinoma patient tissues led to the identification of a DNA damage responsive miR signature called DNA damage sensitive miRs (DDSMs). DDSMs were experimentally validated in the cancerous colon tissues obtained from an independent cohort of colon cancer patients and in multiple cellular systems with high levels of endogenous DNA damage. All the tested DDSMs were transcriptionally upregulated by a common intestine-specific transcription factor, CDX2. Reciprocally, DDSMs were repressed via the recruitment of HDAC1/2-containing complexes onto the CDX2 promoter. These miRs downregulated multiple key targets in the DNA damage response (DDR) pathway, namely BRCA1, ATM, Chk1 (also known as CHEK1) and RNF8. CDX2 directly regulated the DDSMs, which led to increased tumor volume and metastasis in multiple preclinical models. In colon cancer patient tissues, the DDSMs negatively correlated with BRCA1 levels, were associated with decreased probability of survival and thereby could be used as a prognostic biomarker. This article has an associated First Person interview with the first author of the paper.