In an in vitro model of Lymphangioleiomyomatosis (LAM)—a rare destructive lung neoplasm—primary LAM/TSC cells lacking the mTOR regulator tuberin exhibit constitutive mTOR activation that drives cellular senescence and propagates it to healthy pulmonary lung fibroblasts (PLFs) via conditioned medium. The key mediator identified is Interleukin-8 (IL-8), enriched in small extracellular vesicles (sEVs) shed by LAM/TSC cells. Blocking CXCR2, the IL-8 receptor, with the small molecule SB225002 suppressed both autocrine senescence in LAM/TSC cells and paracrine senescence in PLFs.
This finding advances the senescence-spreading hypothesis—that SASP factors can propagate a pathological senescent state through tissues—by demonstrating vesicle-mediated IL-8 delivery as a concrete mechanism in a lung disease context. CXCR2 inhibition has previously shown promise in other SASP-driven conditions, but identifying sEVs as IL-8 cargo vehicles adds a novel delivery dimension that could explain how senescence spreads beyond direct cell contact. Practically, this positions senolytic or senomorphic strategies, particularly CXCR2 antagonism, as rational therapeutic angles for LAM, a disease with very limited treatment options beyond mTOR inhibitors like rapamycin. Limitations are significant: this is an in vitro cell model only, with no animal or patient cohort validation. Whether sEV-packaged IL-8 reaches sufficient concentrations in vivo to drive tissue-level senescence remains undemonstrated. Still, as a mechanistic contribution, this is incremental-to-meaningful work that refines the cellular senescence toolkit for rare lung disease.