Resolution as an active process

For most of the 20th century, inflammation was thought to resolve passively — the body simply stopped producing inflammatory signals once a threat was cleared. Work pioneered by Charles Serhan's laboratory at Harvard overturned this view: resolution is an active, programmed biological phase driven by its own dedicated molecular mediators. The same enzymes that launch inflammation (COX and 5-LOX) later 'class-switch' their output, producing a family of lipid-derived molecules called specialized pro-resolving mediators (SPMs) — including lipoxins, resolvins, protectins, and maresins. These SPMs actively shut down leukocyte recruitment, trigger macrophages to engulf and clear dead neutrophils (efferocytosis), and guide tissue back to homeostasis. When this resolution program fails or stalls, inflammation does not simply persist at its original intensity — it smoulders, becoming the low-grade chronic inflammation linked to cardiovascular disease, inflammatory bowel disease, neurodegeneration, and metabolic syndrome. The clinical implication is significant: existing anti-inflammatory drugs target the initiation phase, leaving the resolution phase therapeutically unaddressed. This review argues that restoring or amplifying resolution — rather than only suppressing initiation — represents a distinct and largely untapped treatment strategy.

• Resolution is an actively orchestrated biological phase, not a passive default state — it requires the production of specific bioactive lipid mediators (SPMs) to proceed.
• COX and 5-LOX enzymes undergo a class-switch from pro-inflammatory eicosanoid production (prostaglandins, leukotrienes) to SPM production (lipoxins, resolvins, protectins, maresins) within hours to days of inflammatory initiation.
• Failure of the resolution phase — rather than excess initiation — is proposed as the mechanistic basis of chronic smouldering inflammation across conditions including IBD, cardiovascular disease, neurodegeneration, and metabolic syndrome.
• Efferocytosis (macrophage-mediated clearance of apoptotic neutrophils) is identified as a central, actively-driven resolution checkpoint regulated by SPMs.
• Key open questions remain unanswered: no validated clinical biomarkers reliably detect resolution-phase failure; pharmacological SPM restoration without omega-3 supplementation is unproven; and the genetic substrate of human resolution deficiency is unknown.

This is a mechanism review article synthesising foundational and contemporary research on resolution biology, drawing primarily on findings from the Serhan laboratory (Harvard) beginning in the late 1990s through the time of publication. No primary experimental cohort, intervention arm, or prospective follow-up period is reported; the study design is a narrative-mechanistic synthesis. Evidence base spans in vitro enzyme biochemistry, animal models of acute inflammation, and early translational SPM studies. As a review, it does not report its own sample size, randomisation, or blinding procedures.

Because this is a mechanism review rather than a primary clinical or interventional study, it cannot establish causality between resolution-phase failure and specific chronic diseases in human populations. The three open questions the authors themselves flag — absence of validated resolution-failure biomarkers, lack of pharmacological SPM restoration strategies independent of omega-3 substrate, and unknown genetic architecture of resolution deficiency — define the frontier this review cannot cross. The next clarifying experiments would include prospective longitudinal studies measuring SPM profiles in patients who develop chronic inflammatory disease versus those who recover fully, and genome-wide association studies designed around resolution-failure phenotypes. The enzyme class-switch model, while well-supported in animal systems, still requires larger-scale confirmation in human tissue contexts.

This article establishes the foundational mechanistic framework that structures much of the resolution-biology corpus on this platform. It directly extends [§20], which characterises the specific SPM molecules — resolvins, protectins, maresins, and lipoxins — whose existence and biological roles are only intelligible against the paradigm shift described here; [§20] can be read as the molecular inventory for the conceptual architecture this review builds. The active-resolution framework also extends [§23], which operationalises the omega-3 index as a clinical biomarker proxy for SPM substrate availability — a measurement tool whose rationale depends entirely on the class-switch mechanism described here. Additionally, the efferocytosis arm of the resolution program described in this article provides direct mechanistic grounding for [§77], which examines efferocytosis-related gene expression in atherosclerosis and implicitly assumes that defective efferocytosis is a resolution-failure event of the kind theorised here.

• Specialized pro-resolving mediators (SPMs)
  Provides the molecular-level complement to this review — where this article establishes that SPMs exist and matter, [id=20] catalogues their structures, biosynthetic pathways, and receptor interactions, making the two articles best read together.
• The omega-3 index as biomarker
  Translates the theoretical class-switch mechanism into a measurable clinical index; comparing the two reveals the gap between mechanistic understanding and validated biomarker practice that this review's open questions explicitly flag.
• Comprehensive analysis of efferocytosis-related genes in diagnosis and immune infiltration in atherosclerosis: based on bulk and single-cell RNA sequencing data
  Applies the efferocytosis concept — one of the active resolution checkpoints described here — to a specific chronic disease context (atherosclerosis), allowing readers to evaluate how well the mechanistic model maps onto real genomic and immunological data.