Toll-Like Receptor-4-Mediated Inflammation is Involved in Intermittent Hypoxia-Induced Lung Injury.

Abstract

Intermittent hypoxia (IH) is a recognized risk factor for multiple organs damage, resulting in lung injury. Its pathophysiology is still poorly understood. Toll-like receptor 4 (TLR4) signaling plays a critical role in host immune response to invading pathogen and non-infectious tissue injury. The role of TLR4-mediated inflammation in IH-induced lung injury was investigated in this study. Lean adult male TLR4-deficient (TLR4-/-) mice and their controls (C57BL/6 mice) were exposed to either IH (FiO2 6-8% for 25s, 150s/cycle, 8h/day) or air (normoxic mice) for 6weeks. Animals were sacrificed after 6-week exposure, and the lung tissues were harvested for morphological and inflammatory analyses. The expression of TLR4 and nuclear factor kappa-B (NF-κB) P65 were examined by real-time quantitative polymerase chain reaction and immunohistochemical method. Serum cytokine levels of interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α) were analyzed by enzyme-linked immunosorbent assay. IH induced morphological and inflammation changes in the lung. IH for 6weeks induced higher expression of TLR4 (C57BL/6-N vs C57BL/6-IH, P < 0.05) and resulted in higher release of TNF-α, IL-6 (P < 0.05), and NF-κB P65 (P < 0.05). These alterations were remitted by TLR4 deletion. TLR4-mediated inflammation plays an important role in the development of IH-induced lung injury in mice, possibly through mechanisms involving nuclear factor-κB. Targeting TLR4/NF-κB pathway could represent a further therapeutic option for sleep apnea patients.