Arachidonic Acid 12-lipoxygenase (ALOX12) Promotes Pulmonary Fibrosis = Arachidonic Acid 12-lipoxygenase (ALOX12) Promotes Pulmonary Fibrosis

다국어 초록 (Multilingual Abstract)

Background
12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) is product of arachidonic acid metabolism through the enzyme of arachidonic acid 12-lipoxygenase (ALOX12) in human platelets or leukocytes. ALOX12 plays an important role in inflammation and oxidation and is involved in development of various human diseases. However, the role of 12(S)-HETE and ALOX12 in the pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unexplored. We investigated the role of ALOX12 in IPF.
Methods
The level of 12-HETE was measured in human plasma (healthy control = 40, IPF = 76) via liquid chromatography-mass spectrometry (LC-MS/MS). The function of 12-HETE and ALOX12 were evaluated in TGF-β1-stimulated human lung fibroblast (MRC-5 cell, primary lung fibroblast) using ALOX12 inhibitor or silencing RNA (siRNA). The anti-fibrotic effects of ALOX12 inhibitor were evaluated in bleomycin-induced mice model of pulmonary fibrosis.
Results
The level of 12-HETE was significantly increased in plasma of IPF patients compared with controls. 12-HETE increased protein expression levels of collagen I and fibronectin in human lung fibroblast. ALOX12 levels were increased in lung tissues of patients with IPF and human lung fibroblasts stimulated by TGF-β1 compared with those of controls. ALOX12 inhibitor and ALOX12 specific siRNA downregulated protein expression levels of collagen I and fibronectin increased by TGF-β1 in human lung fibroblasts. In addition, ALOX12 inhibitor decreased TGF- β1 induced phosphorylation of Smad2/3 in MRC-5 cell. In bleomycin treated mice, ALOX12 inhibitor decreased levels of hydroxyproline in the lung compared of control mice.
Conclusions
Our findings suggest that inhibition of ALOX12 may have anti-fibrotic effects on pulmonary fibrosis, suggesting that ALOX12 is implicated as a potential therapeutic target in IPF.