TABLE 1.
Tissue turnover products cleared from blood mainly by LSECs*, the endocytosis receptor involved in the LSEC uptake, examples of rate of blood clearance of ligands taken up by LSECs following i.v. administration of the ligand, and species examined.
| Ligand | LSEC receptor | References | Examples of injected material (dose, inj. site) | Species | Decay of plasma/blood radioactivity (% eliminated) | References |
| Hyaluronan | Stabilin-2a | Smedsrød et al., 1984; McCourt et al., 1999; Zhou et al., 2000; Politz et al., 2002 | [3H]-hyaluronan (30–32 μg, marginal ear vein) | Rabbit | t1/2 = 2.5–4.5 min (88% uptake in liver at 19 min after injection) | Fraser et al., 1981 |
| 125I-tyramine cellobiose (TC)-labeled hyaluronan (MW = 2.5 × 105) (tail vein) | Rat | t1/2α = 0.9 min (79% uptake in liver at 30 min after injection) | Dahl et al., 1988 | |||
| [3H]-hyaluronan (60–130 μg, cubital vein) | Human | t1/2 = 2.6-5.5min (90% was eliminated from blood after 10 min) | Fraser et al., 1984 | |||
| Chondroitin sulfate | Stabilin-2a | Smedsrød et al., 1985b; Harris and Weigel, 2008 | [3H]-chondroitin sulfate (CS) and 125I-CS proteoglycan | Rat | Clearance rate not examined but the main uptake was in LSECs | Smedsrød et al., 1985b |
| Heparin | Stabilin-2b | Harris et al., 2008, 2009; Øie et al., 2008 | 125I-FITC-labeled unfractionated heparin (0.1 IU/kg, tail vein) | Rat | t1/2 = 1.71 min (71% was recovered in liver after 15 min) | Øie et al., 2008 |
| Nidogen | SR | Smedsrød et al., 1989 | 125I-TC-nidogen (trace amounts, tail vein) | Rat | t1/2 = 2-3 min (78% was recovered in liver after 1 h) | Smedsrød et al., 1989 |
| Alpha chains of types I–V and XI collagen | Mannosec receptor | Smedsrød et al., 1985a; Smedsrød, 1990; Malovic et al., 2007 | 125I-FITC-labeled heat-denatured collagen (50 μg, tail vein) | Rat | t1/2α = 0.8 min (75%) t1/2β = 3.7 min (25%) | Hellevik et al., 1996 |
| 125I-DTAF-collagen (heat-denatured) (0.04 mg/kg, tail vein) | Mouse | t1/2α = 0.51 min (90.25%) t1/2β = 36.9 min (9.75%) | Malovic et al., 2007 | |||
| N-terminal propeptide of types I and III procollagen (PINP and PIIINP) | SR. Stabilin-2 | Smedsrød, 1988; Melkko et al., 1994 | 125I-TC-PINP (5 μg, tail vein) | Rat | t1/2α = 0.59 min (78.5%) t1/2β = 3.3 min (21.5%) | Melkko et al., 1994 |
| C-terminal propeptide of type I procollagen (PICP) | Mannose receptor | Smedsrød et al., 1990a | 125I-TC-PICP (10 μg, tail vein) | Rat | t1/2 = 8.7 min | Smedsrød et al., 1990a |
| Tissue plasminogen activator (tPA) | Mannose receptor | Smedsrød and Einarsson, 1990 | 125I-tPA (1 μg, tail vein) | Rat | t1/2α = 0.6 min (65%) t1/2β = 6.4 min (35%) | Smedsrød and Einarsson, 1990 |
| Lysosomal enzymes | Mannose receptor | Hubbard et al., 1979; Isaksson et al., 1983; Elvevold et al., 2008a | 125I-cathepsin (10 μg, tail vein) | Mouse | t1/2α = 0.9 min (63%) t1/2β = 8.9 min (37%) | Elvevold et al., 2008a |
| 125I-glycosyl asparaginase (trace amounts, tail vein) | Rat | t1/2α = 0.7 min (63%) t1/2β = 3.3 min (37%) | Smedsrød and Tollersrud, 1995 | |||
| 125I-α-mannosidase (trace amounts, jugular vein) | Pig | t1/2 = 5 min (about 60% was recovered in liver, and 18% in lung after 1 h) | Nedredal et al., 2003 | |||
| Formaldehyde-treated serum albumin (FSA)d | SR. Stabilin-1, and stabilin2 | Blomhoff et al., 1984; McCourt et al., 1999; Li et al., 2011 | 125I-FSA (0.1 mg, femoral vein) | Rat | 70% was recovered in LSECs 12 min post injection | Blomhoff et al., 1984 |
| 125I-FSA (2 μg, tail vein) | Mouse | t1/2 = approximately 1–2 mine (77% was recovered in liver after 10 min) | Elvevold et al., 2008a | |||
| 125I-TC-FSA (trace amounts, jugular vein) | Pig | t1/2 = 2 min (about 53% was recovered in liver, and 26% in lung after 1 h) | Nedredal et al., 2003 |
∗A more complete overview of macromolecular ligands removed from the circulation by LSECs is presented in Sørensen et al. (2012, 2015). SR, scavenger receptor.
aThe receptor was named the hyaluronan receptor until 1999 when it was found that scavenger receptor (SR) ligands and hyaluronan (HA) bound to the same receptor on LSECs (McCourt et al., 1999). The receptor was later named stabilin-2 (Politz et al., 2002) [aka HARE (Zhou et al., 2000), FEEL-2 (Tamura et al., 2003)].
bHeparin was found to be a ligand for human stabilin-2 in Harris et al. (2008), and an antibody to the receptor partly inhibited binding of heparin in rat LSECs (Harris et al., 2009) whereas another study in rat did not find heparin binding to stabilin-2 (Øie et al., 2008).
cUptake of collagen alpha-chains was until 2007 thought to occur via a distinct collagen receptor in LSECs. In 2007 it was found that this receptor was identical to the mannose receptor (Malovic et al., 2007). Binding of denatured collagen/collagen alpha-chains occur via the fibronectin type II domain in this receptor (Martinez-Pomares et al., 2006; Napper et al., 2006).
dFSA is a non-physiological ligand that is much used in studies of LSEC function. It is an SR ligand and is internalized both via stabilin-1 and stabilin-2 in LSECs (McCourt et al., 1999; Li et al., 2011).
eThe rate of elimination of 125I-FSA from blood was not calculated in Elvevold et al. (2008a) but from the decay curve in Figure 5 of that reference we have estimated that that about 50% of the radioactivity in blood at 1 min post injection was eliminated after 2 min and more than 80% was eliminated after 5 min.