摘要：a c k g r o u n d: The role of the Nlrp3 inflammasome in non allergic airway hyper responsiveness (AHR) has not previously been reported. Recent evidence supports both interleukin (IL) 1βand short fragments of hyaluronan (HA) as contributors to the biological response to inhaled ozone. oB j e c t i v e: Because extracellular secretion of IL.1βrequires activation of the inflammasome, we investigated the role of the inflammasome proteins ASC, caspase1, and Nlrp3 in the biological response to ozone and HA.Me t h o d s: C57BL/6J wild.type mice and mice deficient in ASC, caspase1, or Nlrp3 were exposed to ozone (1 ppm for 3 hr) or HA followed by analysis of airway resistance, cellular inflammation, and total protein and cyto kines in bronchoalveolar lavage fluid (BALF). Transcription levels of IL.1βand IL.18 were determined in two populations of lung macro phages. In addition, we exam.ined levels of cleaved caspase1 and cleaved IL.1βas markers of inflammasome activation in isolated alveolar macro phages harvested from BALF from HA.treated mice. re s u l t s: We observed that genes of the Nlrp3 inflammasome were required for development of AHR following exposure to either ozone or HA fragments. These genes are partially required for the cellular inflammatory response to ozone. The expression of IL.1βmRNA in alveolar macro.phages was up.regulated after either ozone or HA challenge and was not dependent on the Nlrp3 inflammasome. However, soluble levels of IL.1βprotein were dependent on the inflammasome after challenge with either ozone or HA. HA challenge resulted in cleavage of macrophage.derived caspase1 and IL.1β, suggesting a role for alveolar macrophages in Nlrp3.dependent AHR.co n c l u s i o n s: The Nlrp3 inflammasome is required for the development of ozone.induced reactive airways disease
