Hyaluronan Signaling during Ozone-Induced Lung Injury Requires TLR4, MyD88, and TIRAP

作者：Li Zhuowei^*; Potts Kant Erin N; Garantziotis Stavros; Foster W Michael; Hollingsworth John W

来源：PLos One, 2011, 6(11): e27137.

DOI：10.1371/journal.pone.0027137

Ozone exposure is associated with exacerbation of reactive airways disease. We have previously reported that the damage-associated molecular pattern, hyaluronan, is required for the complete biological response to ambient ozone and that hyaluronan fragments signal through toll-like receptor 4 (TLR4). In this study, we further investigated the role of TLR4 adaptors in ozone-induced airway hyperresponsiveness (AHR) and the direct response to hyaluronan fragments (HA). Using a murine model of AHR, C57BL/6J, TLR4(-/-), MyD88(-/-), and TIRAP(-/-) mice were characterized for AHR after exposure to either ozone (1 ppmx3 h) or HA fragments. Animals were characterized for AHR with methacholine challenge, cellular inflammation, lung injury, and production of pro-inflammatory cytokines. Ozone-exposed C57BL/6J mice developed cellular inflammation, lung injury, pro-inflammatory cytokines, and AHR, while mice deficient in TLR4, MyD88 or TIRAP demonstrated both reduced AHR and reduced levels of pro-inflammatory cytokines including TNF alpha, IL-1 beta, MCP-1, IL-6 and KC. The level of hyaluronan was increased after inhalation of ozone in each strain of mice. Direct challenge of mice to hyaluronan resulted in AHR in C57BL/6J mice, but not in TLR4(-/-), MyD88(-/-), or TIRAP(-/-) mice. HA-induced cytokine production in wild-type mice was significantly reduced in TLR4(-/-), MyD88(-/-), or TIRAP(-/-) mice. In conclusion, our findings support that ozone-induced airway hyperresponsiveness is dependent on the HA-TLR4-MyD88-TIRAP signaling pathway.

• 出版日期2011-11-4