Progressive dysfunction of collecting liver lymphatics during the development of extrahepatic cholestasis

Abstract

Lymphatics are necessary anatomical structures of body systems to maintain tissue fluid and molecular homeostasis and are tightly involved in immune reactions of the body. Transport function of lymphatics is altered during inflammation, which impacts the pathogenesis of many diseases. Despite their importance in liver function, the functional characteristics of liver lymphatic vessels (LLVs) have not been evaluated. In this study we, for the first time, measured the function of LLVs in normal and cholestatic rats following extrahepatic bile duct ligation (BDL). In this study parameters of lymphatic contractility/pumping of isolated, cannulated and pressurized segments of LLVs were determined in male 5 moth old Sprague‐Dawley rats. The following animal groups were used: control, 1, 3 and 7 days, after BDL (BDL1, BDL3 and BDL7) and sham control 3 days after surgery. Segments of LLVs located in close proximity to the liver were dissected for the study. Lymphatic contractility parameters were measured and analyzed in isolated, cannulated and pressurized LLV segments under standard transmural pressures and imposed flow ranges in all groups. Healthy LLVs with outer diameter of ~500±50 μm have significant lymphatic tone (7–9%), moderate contraction amplitude (10–25%), high contraction frequency (14–25 contractions/min) demonstrating therefore strong pumping (4–7 volumes/min). Contractility of LLVs from sham and control group were not significantly different. BDL induced specific changes in tone and phasic contractions of LLVs. BDL caused an increase in vessel size (up to 900±100 μm of outer diameter in BDL7 group), progressive lowering of lymphatic tone over period of time after BDL (up to ~2–3‐fold lower lymphatic tone in BDL7 group). Effects of BDL on lymphatic contraction amplitude were as follows: BDL1‐LLVs contraction amplitude was ~2–2.5 times higher than control, BDL3– back to control values, BDL7– amplitude was 0 (a complete cessation of phasic contractions). At the same time contraction frequency in BDL1 and BDL3 LLVs was ~2–2.2 fold lower than control with no contractions in BDL7 group. Cumulatively, we observed a progressive decline in LLVs' pumping in BDL1 and BDL3 groups with complete lymphatic pump failure in BDL7 group. Additionally, LLVs possess comparatively light flow‐dependent responses, which were ablated by BDL. The data indicate that over the time course of cholestasis, the transport capabilities of LLVs are progressively diminished introducing severe, harmful disturbances in fluid/macromolecular homeostasis of the cholestatic liver, which could alter proper trafficking of immune cells and promote liver inflammation. Further research on underlying mechanisms of liver lymphatic dysfunction will shed light on the pathogenesis of cholestatic liver disease and may reveal novel therapeutic approaches.Support or Funding Information1U01HL123420 (DZ, AG); DK110035 (SG, GA)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.