Enhanced interleukin-18 expression in rodent models of quartz induced fibrosis

Rationale: A long-term inflammatory status is thought to be an essential driver of tissue remodeling leading to fibrosis. The importance of inflammasome signaling in lung tissue has been demonstrated herein. Interleukin-18 (IL-18) has been profoundly described as a potent target in inflammatory and fibrotic diseases. Whether this cytokine is associated with silicosis remains to be elucidated. We aimed to reveal a role for IL-18 in silica induced fibrotic responses in rodents. Methods: Wistar rats and C57BL/6J mice were treated with saline or Dorentruper quartz (DQ12) at doses known to cause persistent inflammation and fibrosis, respectively by intratracheal instillation (5 mg/kg b.w.) or pharyngeal aspiration (100 mg/kg). To investigate the role of the particle surface reactivity, 2 mg of polyvinylpyridine-N-oxide (PVNO) coated quartz was included in the study. At various time points, lungs were analyzed by means of immunohistochemistry to screen for IL-18 expression. In the rat model, mature IL-18 levels were measured in bronchoalveolar lavage fluid (BALF) using Western blot. Results: IL-18 expression was upregulated in quartz-exposed lungs of both species. In the rat model, IL-18 processing was confirmed in the BALF at 3 and 7 days, preceding the course of fibrosis development. Mature IL-18 levels were less increased in lavage of rats treated with surface modified quartz particles. Conclusion: Current data on IL-18 underlie the importance of particle surface reactivity-driven inflammasome activation in quartz exposed lungs. Parallel ongoing in vitro studies concentrate on the molecular mechanism of IL-18 activation by quartz and the role of this cytokine in fibrosis.