Iranian Endodontic Journal

Abstract

Chronic apical periodontitis (AP) has traditionally been attributed to microbial infection and pulp necrosis. Emerging biological and clinical evidence supports the biological plausibility of chronic periapical disease arising from persistent pulpal inflammation through inflammation-mediated pathways. In this integrated model, pulpal inflammation initiated by infectious or non-infectious stimuli progresses corono-apically, potentially contributing to periapical inflammation and bone resorption without microbial colonisation. This review synthesises molecular, immunological, and clinical evidence supporting the biological plausibility of inflammation-driven pathways contributing to chronic AP. Pattern recognition receptors (PRRs), historically regarded as sensors of pathogen-associated molecular patterns (PAMPs), also respond to damage-associated molecular patterns (DAMPs) released by stressed or dying cells. PAMPs and DAMPs converge on innate immune pathways including toll-like receptors (TLRs), NOD-like receptors (NLRs), and inflammasomes amplifying inflammatory signalling. Neuropeptide release, elevated intrapulpal pressure, and apically directed chemotactic gradients may facilitate mediator transport beyond the pulp. In the periapical region, these signals may activate resident cells and promote osteoclastogenesis through interconnected inflammatory and immunological pathways. Collectively, these findings suggest that persistent pulpal inflammation may contribute to chronic AP even in the presence of pulp vitality. Collectively, these findings support inflammation-mediated pathways as a complementary biological mechanism that may contribute to chronic AP in selected clinical scenarios, while recognising microbial infection and pulp necrosis as the predominant drivers of disease.