Roberts Melissa A, Mendez Uziel, Gilbert Ryan J, Keim Alexander P, Goldman Jeremy
Biomedical Engineering Department, Michigan Technological University, Houghton, Michigan 49931, USA.
Lymphat Res Biol. 2012 Sep;10(3):122-8. doi: 10.1089/lrb.2012.0001.
Lymphatic dysfunction in lymphedema results in chronic accumulation of interstitial fluid and life-long tissue swelling. In the absence of restored lymphatic drainage via adequate lymphangiogenesis, the interstitial environment can remodel in ways that decrease the elevated interstitial stress. Presently, relatively little is known about the glycosaminoglycans (GAGs) that become upregulated in the interstitium during lymphedema. We employed a mouse tail model of acute lymphedema that reproduces important features of the chronic human condition to establish a relationship between hyaluronan (HA) and sulfated GAG concentration with tissue swelling. We found that HA was upregulated by tissue injury at day 5 and became upregulated again by skin swelling (HA content increasing by 27% relative to controls at days 15 and 20). Surprisingly, the second phase of HA expression was associated with the declining phase of the tail skin swelling (tail diameter significantly decreasing by 17% from day 10 peak to day 20), demonstrating that HA is upregulated by tissue swelling and may help to counteract the edema in the mouse tail. This finding was confirmed by intradermal injection of an HA degrading enzyme (hyaluronidase) to the swollen tail, which was found to worsen the tail swelling. Sulfated GAGs, including chondroitin sulfate (CS), were not regulated by tissue swelling. The results demonstrate that HA, but not sulfated GAGs, is upregulated in the interstitium by acute tissue swelling. We speculate that HA expression during lymphedema may be part of a natural adaptive mechanism of the interstitial environment to reduce capillary filtration and increase interstitial fluid outflow following lymphatic obstruction and fluid accumulation.
淋巴水肿中的淋巴管功能障碍会导致间质液慢性积聚和组织长期肿胀。在未能通过充分的淋巴管生成恢复淋巴引流的情况下，间质环境会以降低升高的间质压力的方式进行重塑。目前，对于淋巴水肿期间间质中上调的糖胺聚糖（GAGs）了解相对较少。我们采用了一种急性淋巴水肿小鼠尾巴模型，该模型再现了慢性人类疾病的重要特征，以建立透明质酸（HA）和硫酸化GAG浓度与组织肿胀之间的关系。我们发现，HA在第5天因组织损伤而上调，并在皮肤肿胀时再次上调（在第15天和第20天，HA含量相对于对照组增加了27%）。令人惊讶的是，HA表达的第二阶段与尾巴皮肤肿胀的消退阶段相关（尾巴直径从第10天的峰值到第20天显著下降了17%），表明HA因组织肿胀而上调，可能有助于抵消小鼠尾巴中的水肿。通过向肿胀的尾巴皮内注射HA降解酶（透明质酸酶）证实了这一发现，发现这会使尾巴肿胀加剧。包括硫酸软骨素（CS）在内的硫酸化GAGs不受组织肿胀的调节。结果表明，急性组织肿胀会使间质中的HA上调，而硫酸化GAGs则不会。我们推测，淋巴水肿期间HA的表达可能是间质环境的一种自然适应性机制的一部分，可以减少毛细血管滤过，并在淋巴阻塞和液体积聚后增加间质液流出。
