Plasma clearance of rat bikunin: evidence for receptor-mediated uptake

Sjöberg, Mathilda; Blom, Anna M.; Larsson, Bengt; Alston-Smith, J; Sjöquist, Mats; Fries, Erik

doi:10.1042/bj3080881

Cited by 36 publications

(20 citation statements)

References 39 publications

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“…Free BK is cleared through the kidneys by glomerular filtration (35,36) and then partly reabsorbed and catabolized by proximal tubular cells. In our study, increased BK excretion in urine during inflammation was not related to any modification in its behavior in the kidney.…”

Section: Discussionmentioning

confidence: 99%

Urinary Bikunin Determination Provides Insight into Proteinase/Proteinase Inhibitor Imbalance in Patients with Inflammatory Diseases

Mizon¹,

Piva²,

Queyrel³

et al. 2002

Clinical Chemistry and Laboratory Medicine

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Bikunin (BK) is a Kunitz-type proteinase inhibitor responsible for most of the antitryptic activity of urine and so is known as the urinary trypsin inhibitor. As its excretion increases in inflammatory conditions, it is often considered to be a positive acute phase protein (APP). However, the gene for BK is downregulated in inflammation. In human plasma the major part of BK is covalently linked through a glycosaminoglycan chain to one or two homologous peptide heavy chains, thus forming high molecular weight proteinase inhibitors called pre-alpha-inhibitor (PalphaI) and inter-alpha-inhibitor (IalphaI), respectively. The C-terminal parts of these heavy chains are very sensitive to proteolysis. Neutrophil proteinases in particular are able to release from IalphaI and PalphaI BK (M, about 25,000) which retains its antitryptic activity and is quickly excreted in urine. It was therefore an early supposition that the higher urinary excretion of BK occurring during inflammatory diseases should be, at least in some respect, related to a partial proteolysis of IalphaI and PalphaI. In this study we observed that BK, determined as antitryptic activity, was clearly increased in urine from 35 patients with inflammatory diseases varying in origin and severity (76.5 +/- 75.5 IU/g vs. reference value <10 IU/g creatinine). This increase seems mainly to be associated with polymorphonuclear leukocyte activation, monitored by human leukocyte elastase (HLE) determination rather than with the acute phase response assessed by C-reactive protein (CRP) measurement. For all the patients we found that the urinary levels of BK and serum concentration of intact IalphaI correlated inversely (r=-0.36; p=0.03), in agreement with the presumed precursor-product relationship linking IalphaI and BK. We also proved that urinary BK was significantly higher, and serum IalphaI was significantly lower, in samples with plasma HLE values above the reference: 90 microg/l. Taken together, our results demonstrate that BK, the urinary excretion of which is increased in inflammatory conditions, originates, at least partly, from IalphaI and PalphaI by proteolytic cleavage. Consequently, urinary BK determination provides information on the severity of systemic proteolysis occurring in inflammation. We also demonstrated that during inflammatory diseases IalphaI and PalphaI concentrations in serum are dependent on their increased utilization as well as on the regulation of their biosynthesis.

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Section: Discussionmentioning

confidence: 99%

Urinary Bikunin Determination Provides Insight into Proteinase/Proteinase Inhibitor Imbalance in Patients with Inflammatory Diseases

Mizon¹,

Piva²,

Queyrel³

et al. 2002

Clinical Chemistry and Laboratory Medicine

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“…This was, however, not included in the calculation of θ for bikunin. It has previously been determined in mice that bikunin does not form aggregates or split products in plasma (Sjoberg et al. 1995).…”

Section: Methodsmentioning

confidence: 99%

Glomerular sieving of three neutral polysaccharides, polyethylene oxide and bikunin in rat. Effects of molecular size and conformation

et al. 2007

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“…Thus, it is still possible to compare the t 1/2 of sL-selectin with that of other plasma proteins. Small molecular mass proteins such as IL-2 and bikunin have reported t 1/2 of 4 and 10 min, respectively, due to rapid kidney clearance (53,54). Because sL-selectin is a relatively high molecular mass protein, it would not be expected to be removed to any significant amount by filtration in the kidney.…”

Section: Discussionmentioning

confidence: 99%

A Functional Role for Circulating Mouse L-Selectin in Regulating Leukocyte/Endothelial Cell Interactions In Vivo

Poe

Kadono

et al. 2002

The Journal of Immunology

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L-selectin mediates the initial capture and subsequent rolling of leukocytes along inflamed vascular endothelium and mediates lymphocyte migration to peripheral lymphoid tissues. Leukocyte activation induces rapid endoproteolytic cleavage of L-selectin from the cell surface, generating soluble L-selectin (sL-selectin). Because human sL-selectin retains ligand-binding activity in vitro, mouse sL-selectin and its in vivo relevance were characterized. Comparable with humans, sL-selectin was present in adult C57BL/6 mouse sera at ∼1.7 μg/ml. Similar levels of sL-selectin were present in sera from multiple mouse strains, despite their pronounced differences in cell surface L-selectin expression levels. Adhesion molecule-deficient mice prone to spontaneous chronic inflammation and mice suffering from leukemia/lymphoma had 2.5- and 20-fold increased serum sL-selectin levels, respectively. By contrast, serum sL-selectin levels were reduced by 70% in Rag-deficient mice lacking mature lymphocytes. The majority of serum sL-selectin had a molecular mass of 65–75 kDa, consistent with its lymphocyte origin. Slow turnover may explain the relatively high levels of sL-selectin in vivo. The t1/2 of sL-selectin, assessed by transferring sera from wild-type mice into L-selectin-deficient mice and monitoring serum sL-selectin levels by ELISA, was >20 h, and it remained detectable for longer than 1 wk. Short-term in vivo lymphocyte migration assays demonstrated that near physiologic levels (∼0.9 μg/ml) of sL-selectin decreased lymphocyte migration to peripheral lymph nodes by >30%, with dose-dependent inhibition occurring with increasing sL-selectin concentrations. These results suggest that sL-selectin influences lymphocyte migration in vivo and that the increased sL-selectin levels present in certain pathologic conditions may adversely affect leukocyte migration.

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Plasma clearance of rat bikunin: evidence for receptor-mediated uptake

Cited by 36 publications

References 39 publications

Urinary Bikunin Determination Provides Insight into Proteinase/Proteinase Inhibitor Imbalance in Patients with Inflammatory Diseases

Urinary Bikunin Determination Provides Insight into Proteinase/Proteinase Inhibitor Imbalance in Patients with Inflammatory Diseases

Glomerular sieving of three neutral polysaccharides, polyethylene oxide and bikunin in rat. Effects of molecular size and conformation

A Functional Role for Circulating Mouse L-Selectin in Regulating Leukocyte/Endothelial Cell Interactions In Vivo

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