Biochemical Landscapes of Burger’s Diseaswe: The Interplay Between Nitric Oxide Synthase Patways, Eicasanoid Metabolism, And Stress Hormone Profiles

Buerger’s disease, clinically classified as Thromboangiitis Obliterans (TAO), is a non-atherosclerotic, highly inflammatory, and segmental occlusive peripheral vascular disorder. It predominantly affects the small and medium-sized arteries, veins, and nerves of the distal extremities in young, male heavy tobacco users. While the absolute clinical link between tobacco exposure and TAO is undeniable, the precise cellular and systemic biochemical anomalies driving its pathogenesis remain complex and multi-faceted. Recent molecular evidence shifts focus toward a triad of interconnected systemic perturbations: endothelial nitric oxide synthase (NOS) down-regulation, dysregulated eicosanoid and prostanoid synthesis, and exaggerated stress hormone/catecholaminergic profiles. This comprehensive review examines the complex biochemical landscapes of Buerger’s disease by evaluating the molecular interplay between distinct nitric oxide synthase pathways, eicosanoid metabolism alterations, and neuroendocrine stress hormone systems to uncover potential diagnostic markers and targeted therapeutic pathways. A methodical review of peer-reviewed articles, case-control studies, and clinical data published up to 2026 was performed across engines including PubMed, Web of Science, and Google Scholar. Academic literature was filtered using specific search terms including "Buerger disease", "Thromboangiitis Obliterans", "nitric oxide synthase", "eicosanoids", and "stress hormones". Studies investigating standard macrovascular atherosclerosis or generalized venous thrombosis without a verified diagnosis of TAO were systematically excluded to preserve microvascular precision. The pathological cascade of TAO is characterized by severe endothelial dysfunction and impaired vascular tone modulation. Under normal conditions, endothelial nitric oxide synthase (eNOS) maintains microvascular dilation and inhibits platelet activation. In TAO, genetic polymorphisms and active nicotine exposure down-regulate cytoprotective eNOS. This causes a drop in nitric oxide (NO) bioavailability and triggers the up-regulation of inducible nitric oxide synthase (iNOS) within the vascular walls. The excess NO produced by iNOS reacts rapidly with reactive oxygen species (ROS) to form toxic peroxynitrite, causing local nitrosative stress, lipid peroxidation, and endothelial damage. Concurrently, eicosanoid pathways shift toward a pro-thrombotic profile; the synthesis of protective prostacyclins drops significantly, while thromboxane A2 (TXA2) production increases, accelerating physical thrombus formation and luminal narrowing. This cellular imbalance is further worsened by systemic neuroendocrine activation. Chronic heavy nicotine use overactivates the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic circuits, elevating circulating levels of epinephrine, norepinephrine, and cortisol. These stress hormones induce severe vasoconstriction and heighten platelet aggregation, forming a persistent biochemical loop that results in critical limb ischemia, intractable rest pain, and ischemic tissue necrosis. Buerger’s disease involves an intricate combination of vascular enzyme dysregulation, lipid mediator imbalances, and chronic neuroendocrine stress responses. Moving beyond standalone clinical evaluation toward multi-analyte biochemical panels—measuring local iNOS/eNOS ratios, plasma eicosanoid profiles, and circulating catecholamines—offers a non-invasive strategy for monitoring early microvascular damage, tracking disease activity, and optimizing targeted multi-mechanistic therapies.