How does chronic prostatic inflammation mechanistically drive glandular hyperplasia at the molecular and cellular level?
Executive summary
Chronic prostatic inflammation drives glandular hyperplasia through a sustained immune-stromal-epithelial cross talk in which infiltrating immune cells secrete cytokines and chemokines that activate proliferative signaling, induce reactive stroma and myofibroblast differentiation, and create oxidative and hypoxic microenvironments that favor epithelial proliferation and altered differentiation [1] [2] [3]. While multiple molecular mediators have been implicated—IL‑8/IL‑6/IL‑17, MCP‑1, COX‑2, NF‑κB, HIF‑1α, TGF‑β and growth factors like FGF and IGF—there is no single proven linear pathway; instead, evidence supports a networked wound‑repair–like process that can be hormone‑modulated and heterogeneous among patients [4] [5] [6].
1. The cellular cast: chronically activated T cells, macrophages and epithelial sources
Histology and immunologic profiling of BPH tissues repeatedly show dense infiltrates composed largely of chronically activated T‑lymphocytes and macrophage populations that both respond to and secrete pro‑growth signals; epithelial and progenitor cells within BPH lesions themselves also secrete chemokines (for example IL‑8 and MCP‑1) that recruit and sustain this infiltrate, establishing a self‑reinforcing inflammatory niche [7] [1] [4].
2. Cytokine and chemokine wiring that turns inflammation into growth
Once established, the inflammatory microenvironment elevates cytokines and chemokines—IL‑8, IL‑6, IL‑17, MCP‑1/CCL2—that activate canonical proliferation pathways (NF‑κB, MAPK, PI3K/Akt) in both epithelial and stromal compartments and induce expression of anti‑apoptotic mediators such as Bcl‑2 and enzymes like COX‑2, collectively increasing cell survival and cell cycle progression that manifest as glandular hyperplasia [2] [3] [8].
3. Oxidative stress, hypoxia and epithelial plasticity: engines of atypical proliferation
Inflammatory cells generate reactive oxygen and nitrogen species that cause DNA and tissue damage and stimulate compensatory proliferation; simultaneous microvascular changes and immune‑mediated hypoxia promote HIF‑1α expression, which can drive EMT‑related programs (via Twist and other effectors) and shift epithelial behavior toward hyperplasia and altered differentiation—links supported by animal and molecular studies though causality to human BPH progression remains incompletely mapped [2] [9] [10].
4. Reactive stroma, myofibroblasts and extracellular matrix remodeling
Inflammation converts normal stroma into a reactive phenotype: fibroblasts differentiate into α‑SMA‑expressing myofibroblasts under TGF‑β1 signaling, secrete ECM components and matricellular proteins (e.g., tenascin‑C), and produce growth factors (FGF‑2, FGF‑7, IGF‑1) that act in paracrine fashion on epithelium and smooth muscle, thereby structurally and functionally supporting nodular growth and glandular expansion [11] [12] [4].
5. Where inflammation meets hormones: androgen interactions and androgen‑independent growth
Although traditional models emphasize androgens in prostate growth, chronic inflammation can promote androgen‑independent proliferative signaling through cytokine‑driven pathways and stromal paracrine factors; conversely, androgen receptor signaling modulates immune cell effects and can influence macrophage‑epithelial interactions, making BPH a disease where hormonal milieu and inflammation intersect rather than act in isolation [5] [3] [1].
6. An integrated mechanistic model and the limits of current evidence
The prevailing mechanistic model proposes chronic or recurrent tissue injury → immune cell recruitment and cytokine/chemokine secretion → oxidative/hypoxic stress and activation of NF‑κB/HIF‑1α signalling → stromal activation/myofibroblast recruitment and growth factor release → epithelial hyperproliferation and glandular hyperplasia; this network view is supported by histology, animal models and molecular profiling, but definitive human causal chains, temporal ordering, and which pathways are dominant in individual patients remain unresolved—many reviews explicitly note that specific upstream triggers and interpatient heterogeneity are still unknown [6] [12] [10].
7. Clinical and translational implications, and contrasting viewpoints
Therapeutic strategies that target inflammation (COX‑2 modulation, vitamin D analogues, HIF‑1α inhibitors, anti‑cytokine approaches) show mechanistic promise in preclinical and some clinical settings, but meta‑analyses and reviews caution that BPH is multifactorial—some nodules are stromal‑dominant, others epithelial—and inflammation may be one of several co‑drivers rather than the sole cause, so patient selection and mechanistic biomarkers will be essential to translate these insights [5] [13] [4].