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Apoptosis resistance in fibroblasts precedes progressive scarring in pulmonary fibrosis and is partially mediated by Toll-like receptor 4 activation.

Inhalation of environmental toxicants such as cigarette smoke, metal or wood dust, silica, or asbestos is associated with increased risk for idiopathic pulmonary fibrosis (IPF). IPF involves progressive scarring of lung tissue, which interferes with normal respiration and is ultimately fatal; however, the complex cellular mechanisms of IPF pathogenesis remain unclear. Fibroblast apoptosis is essential in normal wound healing but is dysregulated in IPF. Recent studies suggest that Toll-like receptor 4 (TLR4) is key in the onset of IPF. Here, radiation-induced PF was used as a model for IPF because it very closely mimics the progressive and intractable nature of IPF. Female C57BL/6J (C57) and C57BL/6J TLR4-/- mice were exposed to a single dose of 13 Gy whole-thorax ionizing radiation. Although both strains showed similar levels of immediate radiation-induced damage, C57 mice exhibited more extensive fibrosis at 22 wk post-irradiation (PI) than TLR4-/- mice. Isolated C57 primary mouse lung fibroblasts (1° MLFs) showed decreased apoptosis susceptibility as early as 8 wk PI, a phenotype that persisted for the remainder of the radiation response. TLR4-/- 1° MLFs did not exhibit significant apoptosis resistance at any point. Systemic release of HMGB1, a TLR4 agonist, during the pneumonitis phase of the radiation response may act through TLR4 to contribute to fibroblast apoptosis resistance and thus interfere with wound resolution. These findings demonstrate that apoptosis resistance occurs earlier in PF pathogenesis than previously assumed, and that TLR4 signaling is a key mediator in this process.