Scallan Joshua P, Bouta Echoe M, Rahimi Homaira, Kenney H Mark, Ritchlin Christopher T, Davis Michael J, Schwarz Edward M
Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, United States.
Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States.
Front Physiol. 2021 Sep 27;12:745096. doi: 10.3389/fphys.2021.745096. eCollection 2021.
Recent studies demonstrated lymphangiogenesis and expansion of draining lymph nodes during chronic inflammatory arthritis, and lymphatic dysfunction associated with collapse of draining lymph nodes in rheumatoid arthritis (RA) patients and TNF-transgenic (TNF-Tg) mice experiencing arthritic flare. As the intrinsic differences between lymphatic vessels afferent to healthy, expanding, and collapsed draining lymph nodes are unknown, we characterized the behavior of popliteal lymphatic vessels (PLVs) from WT and TNF-Tg mice. We also interrogated the mechanisms of lymphatic dysfunction through inhibition of nitric oxide synthase (NOS). Popliteal lymph nodes (PLNs) in TNF-Tg mice were phenotyped as Expanding or Collapsed by ultrasound and age-matched to WT littermate controls. The PLVs were harvested and cannulated for functional analysis over a relatively wide range of hydrostatic pressures (0.5-10 cmHO) to quantify the end diastolic diameter (EDD), tone, amplitude (AMP), ejection fraction (EF), contraction frequency (FREQ), and fractional pump flow (FPF) with or without NOS inhibitors Data were analyzed using repeated measures two-way ANOVA with Bonferroni's test. Real time videos of the cannulated PLVs demonstrated the predicted phenotypes of robust vs. weak contractions of the WT vs. TNF-Tg PLV, respectively. Quantitative analyses confirmed that TNF-Tg PLVs had significantly decreased AMP, EF, and FPF vs. WT ( < 0.05). EF and FPF were recovered by NOS inhibition, while the reduction in AMP was NOS independent. No differences in EDD, tone, or FREQ were observed between WT and TNF-Tg PLVs, nor between Expanding vs. Collapsed PLVs. These findings support the concept that chronic inflammatory arthritis leads to NOS dependent and independent draining lymphatic vessel dysfunction that exacerbates disease, and may trigger arthritic flare due to decreased egress of inflammatory cells and soluble factors from affected joints.
近期研究表明，在慢性炎症性关节炎期间，引流淋巴结会发生淋巴管生成和肿大，而类风湿性关节炎（RA）患者和经历关节炎发作的肿瘤坏死因子转基因（TNF-Tg）小鼠会出现与引流淋巴结塌陷相关的淋巴功能障碍。由于流向健康、肿大和塌陷引流淋巴结的淋巴管之间的内在差异尚不清楚，我们对野生型（WT）和TNF-Tg小鼠的腘窝淋巴管（PLV）行为进行了表征。我们还通过抑制一氧化氮合酶（NOS）来探究淋巴功能障碍的机制。通过超声将TNF-Tg小鼠的腘窝淋巴结（PLN）表型鉴定为肿大或塌陷，并使其年龄与野生型同窝对照匹配。收集PLV并插管，在相对较宽的静水压力范围（0.5 - 10 cmH₂O）内进行功能分析，以量化舒张末期直径（EDD）、张力、振幅（AMP）、射血分数（EF）、收缩频率（FREQ）和分数泵流量（FPF），同时使用或不使用NOS抑制剂。数据采用重复测量双向方差分析和Bonferroni检验进行分析。插管PLV的实时视频分别显示了WT与TNF-Tg PLV的强收缩与弱收缩的预测表型。定量分析证实，与WT相比，TNF-Tg PLV的AMP、EF和FPF显著降低（P < 0.05）。NOS抑制可使EF和FPF恢复，而AMP的降低与NOS无关。WT和TNF-Tg PLV之间，以及肿大与塌陷PLV之间，在EDD、张力或FREQ方面均未观察到差异。这些发现支持了这样一种观点，即慢性炎症性关节炎会导致依赖和不依赖NOS的引流淋巴管功能障碍，从而加剧疾病，并可能由于受影响关节中炎症细胞和可溶性因子的流出减少而引发关节炎发作。
