抄録
Inhaled form of polyhexamethylene guanidine (PHMG) can induce pulmonary fibrosis. NADPH oxidases (Nox) are among ROS-producing enzymes, it is known to be responsible for tissue injury associated with several lung pathologies. To determine whether Nox2 isoform of NADPH oxidase participate in the progression of lung damage by PHMG, we investigated contribution to PHMG-induced lung injury a using Nox2 deficient mice. Wild-type (WT) and Nox2 knockout (KO) mice were treated with a single intratracheal instillation of 1.1 mg/kg PHMG and sacrificed at 2 and 15 days respectively. At 2 days, the PHMG-induced acute inflammatory response (increased neutrophil count in bronchoalveolar lavage fluid (BALF)) was significantly increased in both WT and Nox2 KO mice, but the expression of proinflammatory genes such as IL-6 and IL-1β were increased significantly in the lungs of Nox2 KO mice than WT mice. In addition, PHMG treatment reduced the expression of Nox family (1 -2, -3 and -4) mRNA in the lung of WT mice. At 15 days, lung histopathology, hydroxyproline content, number of total cell and macrophage in BALF, and the expression of profibrogenic genes such as MMP-12 and fibronectin demonstrated that PHMG-treated Nox2 KO mice markedly diminished compared with PHMG-treated WT mice. Notably, only the expression of Nox2 was increased by PHMG, in contrast to day 2. These results suggest that Nox2 may plays a crucial role in PHMG-induced lung injury, and it is an important signaling molecule leading to PHMG-induced pulmonary fibrosis by regulating the expression of profibrogenic genes.
PHMG暴露による肺線維化における線維化関連遺伝子の発現誘導にNox2が関与している可能性が考えられる。
