title: In vivo quantification of lymph viscosity and pressure in lymphatic vessels and draining lymph nodes of arthritic joints in mice.
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 cmH2O; P < 0.01), which dramatically increased to 9.92 ± 1.79 cmH2O 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 cmH2O; P < 0.01), which dropped to 2.61 ± 0.72 cmH2O (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 LPP during PLN collapse are consistent with decreased drainage from the joint during arthritic flare, and validate these biomarkers of RA progression and possibly other chronic inflammatory conditions.
authors.affiliation: The Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Box 665, Rochester, NY 14642, USA.  edward_schwarz@urmc.rochester.edu.
authors.forename: Echoe M
authors.initials: EM
authors.lastname: Bouta
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Wood
authors.forename: Edward B
authors.initials: EB
authors.lastname: Brown
authors.forename: Homaira
authors.initials: H
authors.lastname: Rahimi
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Ritchlin
authors.forename: Edward M
authors.initials: EM
authors.lastname: Schwarz
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000209:etiology / Q000503:physiopathology*; D001172:Arthritis, Rheumatoid / Q000209:etiology / Q000503:physiopathology*; D018450:Disease Progression; D036681:Fluorescence Recovery After Photobleaching; D008196:Lymph / Q000502:physiology*; D008198:Lymph Nodes / Q000502:physiology*; D042601:Lymphatic Vessels / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011312:Pressure; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014783:Viscosity
chemical_list: D014409:Tumor Necrosis Factor-alpha