Young Karen C, Hussein Sameh M A, Dadiz Rita, deMello Daphne, Devia Carlos, Hehre Dorothy, Suguihara Cleide
Department of Pediatrics/Division of Neonatology and Batchelor Children's Research Institute, University of Miami, Miller School of Medicine, Miami, FL 33101, USA.
Exp Lung Res. 2010 Mar;36(2):111-9. doi: 10.3109/01902140903171610.
Current data suggest that Toll-like receptor 4 (TLR4), a key molecule in the innate immune response, may also be activated following tissue injury. Activation of this receptor is known to induce the production of several proinflammatory cytokines. Given that pulmonary inflammation has been shown to be a key contributor to chronic hypoxia-induced pulmonary vascular remodeling, the authors hypothesized that TLR4-deficient mice would be less susceptible to pulmonary hypertension (PH) as compared to mice with intact TLR4. TLR4-deficient and TLR4-intact strains of inbred mice were exposed to 4, 8, and 16 weeks of hypoxia (0.10 FiO(2)) or normoxia (0.21 FiO(2)) in a normobaric chamber. After chronic hypoxic exposure, TLR4-intact mice developed significant PH evidenced by increased right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary artery medial thickening. In contrast, TLR4-deficient mice had no significant change in any of these parameters and this was associated with decreased pulmonary vascular inflammatory response as compared to the TLR4-intact mice. These results suggest that TLR4 deficiency may decrease the susceptibility to developing PH by attenuating the pulmonary vascular inflammatory response to chronic hypoxia.
目前的数据表明，Toll样受体4（TLR4）作为先天性免疫反应中的关键分子，在组织损伤后也可能被激活。已知该受体的激活会诱导多种促炎细胞因子的产生。鉴于肺部炎症已被证明是慢性缺氧诱导的肺血管重塑的关键因素，作者推测与TLR4完整的小鼠相比，TLR4缺陷型小鼠对肺动脉高压（PH）的易感性较低。将TLR4缺陷型和TLR4完整型近交系小鼠置于常压低氧舱中，分别暴露于4周、8周和16周的低氧环境（FiO₂为0.10）或常氧环境（FiO₂为0.21）。经过慢性低氧暴露后，TLR4完整型小鼠出现了明显的肺动脉高压，表现为右心室收缩压升高、右心室肥厚和肺动脉中层增厚。相比之下，TLR4缺陷型小鼠在这些参数上均无显著变化，并且与TLR4完整型小鼠相比，其肺血管炎症反应有所减轻。这些结果表明，TLR4缺陷可能通过减弱对慢性缺氧的肺血管炎症反应来降低发生肺动脉高压的易感性。
