Measuring intranodal pressure and lymph viscosity to elucidate mechanisms of arthritic flare and therapeutic outcomes

Bouta, Echoe M.; Wood, Ronald W.; Perry, Seth W.; Brown, Edward B.; Ritchlin, Christopher T.; Xing, Lianping; Schwarz, Edward M.

doi:10.1111/j.1749-6632.2011.06237.x

Cited by 15 publications

(19 citation statements)

References 20 publications

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“…Diffusion coefficient and lymph speed measurements were performed as described previously (Bouta et al . ). Briefly, a tunable mode‐locked Ti:Sapphire laser (Mai Tai; Spectra Physics, Mountain View, CA, USA), yielding 80‐fs pulses at a repetition rate of 100 MHz was used to monitor the sample at a low power while keeping focal volume consistent throughout the experiment.…”

Section: Methodsmentioning

confidence: 97%

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In vivo quantification of lymph viscosity and pressure in lymphatic vessels and draining lymph nodes of arthritic joints in mice

Bouta

Wood

Brown

et al. 2014

The Journal of Physiology

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Key pointsr Previously, it was found that the popliteal lymph node (PLN) enlarges during the pre-arthritic 'expanding' phase, and then 'collapses' with adjacent knee flare and is associated with the loss of the intrinsic lymphatic pulse.r However, the mechanisms responsible are unknown and we therefore developed in vivo methods to measure lymph viscosity, lymphatic pumping pressure (LPP) in the lymphatic vessels afferent to the PLN, and lymph node pressure (LNP).r Multiphoton fluorescence recovery after photobleaching (MP-FRAP) was used to calculate lymph viscosity and speed; no difference was found among mice with wild-type (WT), expanding or collapsed PLN in lymph viscosity, but lymph speed was found to be decreased in mice with collapsed PLN compared to WT and expanding PLN mice.r LPP was measured indirectly by slowly releasing a pressurized cuff occluding ICG fluorescent dye; we found that mice with expanding PLN exhibit a higher LPP compared to WT and mice with collapsed PLN show an extremely low LPP.r Direct measurement of LNP demonstrated a decrease in expanding PLN versus WT pressure, which dramatically increased in collapsed PLN.r The decrease in lymphatic flow and loss of LPP during PLN collapse are consistent with decreased drainage from the joint during arthritic flare, and validate these biomarkers of rheumatoid arthritis progression and possibly other chronic inflammatory conditions Abstract Rheumatoid arthritis (RA) is a chronic inflammatory joint disease with episodic flares. In TNF-Tg mice, a model of inflammatory-erosive arthritis, the popliteal lymph node (PLN) enlarges during the pre-arthritic 'expanding' phase, and then 'collapses' with adjacent knee flare associated with the loss of the intrinsic lymphatic pulse. As the mechanisms responsible are unknown, we developed in vivo methods to quantify lymph viscosity and pressure in mice with wild-type (WT), expanding and collapsed PLN. While no differences in viscosity were detected via multiphoton fluorescence recovery after photobleaching (MP-FRAP) of injected FITC-BSA, a 32.6% decrease in lymph speed was observed in vessels afferent to collapsed PLN (P < 0.05). Direct measurement of intra-lymph node pressure (LNP) demonstrated a decrease in expanding PLN versus WT pressure (3.41 ± 0.43 vs. 6.86 ± 0.56 cmH 2 O; P < 0.01), which dramatically increased to 9.92 ± 1.79 cmH 2 O in collapsed PLN. Lymphatic pumping pressure (LPP), measured indirectly by slowly releasing a pressurized cuff occluding indocyanine green (ICG), demonstrated an increase in vessels afferent to expanding PLN versus WT (18.76 ± 2.34 vs. 11.04 ± 1.47 cmH 2 O; P < 0.01), which dropped to 2.61 ± 0.72 cmH 2 O (P < 0.001) after PLN collapse. Herein, we document the first in vivo measurements of murine lymph viscosity and lymphatic pressure, and provide evidence to support the hypothesis that lymphangiogenesis and lymphatic transport are compensatory mechanisms to prevent synovitis via increased drainage of inflamed joints. Furthermore, the decrease in lymphatic flow and loss of LP...

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Section: Methodsmentioning

confidence: 97%

“…Pressure measurements were performed as described previously (Bouta et al . ). Briefly, TNF‐Tg mice and their WT littermates (ages 4–10 months) were injected with 30 μl of 1% Evan's Blue (Sigma Aldrich) in the hind footpad for initial visualization the PLN.…”

Section: Methodsmentioning

confidence: 97%

In vivo quantification of lymph viscosity and pressure in lymphatic vessels and draining lymph nodes of arthritic joints in mice

Bouta

Wood

Brown

et al. 2014

The Journal of Physiology

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“…In an effort to better understand the mechanism of PLN collapse, methods were developed to measure popliteal lymph node pressure (LNP), lymphatic pumping pressure (LPP) and lymph viscosity and speed [44, 45]. Multiphoton fluorescence after photobleaching (MP-FRAP) of injected FITC-BSA was used to calculate the lymph viscosity and speed [46].…”

Section: Measurement Of Lymph Node Pressure Lymphatic Pumping Prementioning

confidence: 99%

The role of the lymphatic system in inflammatory-erosive arthritis

Bouta

et al. 2015

Seminars in Cell & Developmental Biology

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Rheumatoid arthritis (RA) is a prevalent inflammatory joint disease with enigmatic flares, which causes swelling, pain, and irreversible connective tissue damage. Recently, it has been demonstrated in murine models of RA that the popliteal lymph node (PLN) is a biomarker of arthritic flare, as it “expands” in size and contrast enhancement during a prolonged asymptomatic phase, prior to when it “collapses” with accelerated synovitis and joint erosion. This PLN collapse is associated with adjacent knee flare, decreases in PLN volume and contrast enhancement, lymphatic pulse and pumping pressure, and an increase in PLN pressure. Currently, it is known that PLN collapse is accompanied by a translocation of B cells from the follicles to the sinuses, effectively clogging the lymphatic sinuses of the PLN, and that B cell depletion therapy ameliorates arthritic flare by eliminating these B cells and restoring passive lymphatic flow from inflamed joints. Here we review the technological advances that have launched this area of research, describe future directions to help elucidate the potential mechanism of PLN collapse, and speculate on clinical translation towards new diagnostics and therapies for RA.

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“…Mature LVs transport these factors and cells to lymph nodes. The draining function of the synovial lymphatic system can be monitored by numerous imaging modalities that we have developed, such as near-infrared lymphatic imaging to measure pluses/contraction and tracer clearance of mature LVs efferent joints [6,7]. Our ndings demonstrated that the synovial lymphatic system is closely related to the progression and are of arthritic joints, and its draining function is impaired in RA joints [8].…”

Section: Introductionmentioning

confidence: 80%

Lymphatic Muscle Cells Contribute to Dysfunction of the Synovial Lymphatic System in Inflammatory Arthritis in Mice

Liang

Zhang²,

Xu³

et al. 2020

Preprint

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Background. We previous studies reveal impaired draining function of the synovial lymphatic vessel (LV) contributes to inflammatory arthritis, but the cellular and molecular mechanisms involved are not fully understood.Objective. To investigate the involvement of lymphatic muscle cells (LMCs) in mediating impaired LV function in inflammatory arthritis.Methods. TNF transgenic (TNF-Tg) arthritic mice were used. Structure and function of the LVs that drain the hind limbs were examined by whole-mount immunofluorescence staining, electron microscope, and near-infrared lymphatic imaging. Primary LMCs were treated with TNF, and the changes in proliferation, apoptosis, and functional gene expression were assessed. Roles of the herbal drug, Panax Notoginseng Saponins (PNS), in arthritis and LVs were studied.Results. TNF-Tg mice developed ankle arthritis with age, which was associated with abnormalities of LVs: 1) dilated capillary LVs with few branch points; 2) mature LVs with reduced LMC coverage and draining function; 3) degenerative and apoptotic appearance of LMCs. TNF caused LMC apoptosis, reduced expression of muscle functional genes, and promoted the production of nitric oxide (NO) by lymphatic endothelial cells (LECs). PNS attenuated arthritis, restored LMC coverage and draining function of mature LVs, inhibited TNF-mediated NO expression, and reduced LMC apoptosis.Conclusion. The impaired draining function of LVs in TNF-Tg mice involves LMC apoptosis. TNF promotes LMC death directly and indirectly via NO production by LECs. PNS attenuates arthritis, improves LVs, and prevents TNF-induced LMC apoptosis by inhibiting NO production of LECs. LMCs contribute to the dysfunction of synovial LVs in inflammatory arthritis.

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Measuring intranodal pressure and lymph viscosity to elucidate mechanisms of arthritic flare and therapeutic outcomes

Cited by 15 publications

References 20 publications

In vivo quantification of lymph viscosity and pressure in lymphatic vessels and draining lymph nodes of arthritic joints in mice

In vivo quantification of lymph viscosity and pressure in lymphatic vessels and draining lymph nodes of arthritic joints in mice

The role of the lymphatic system in inflammatory-erosive arthritis

Lymphatic Muscle Cells Contribute to Dysfunction of the Synovial Lymphatic System in Inflammatory Arthritis in Mice

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