Lipopolysaccharide (LPS) may cause sepsis when it enters the blood circulation. The toxic moiety of LPS is the well-preserved lipid A part. Lipid A contains two phosphate groups attached to diglucosamine, which are crucial for the many biological activities of LPS. In previous studies we found that alkaline phosphatase (AP) was able to dephosphorylate LPS. To test whether LPS-dephosphorylation can be used for intervention during sepsis, we investigated the effects of Salmonella minnesota Re 595 LPS and its dephosphorylated counterpart monophosphoryl lipid A (MPLA) on macrophage activation in vivo and in vitro. Exposure of RAW264.7 cells to LPS induced high levels of tumor necrosis factor (TNFalpha) and nitric oxide (NO), whereas MPLA elicited no response. LPS in vivo induced a significant rise in TNFalpha levels in mice and an enhanced inflammatory cell influx in the lung, whereas MPLA did not. Having shown the relevance of this particular phosphate group of LPS, we subsequently explored the LPS-dephosphorylating ability of AP in different tissues, and the effect of AP administration in mice challenged with LPS. Histochemical data show that AP dephosphorylated native LPS in all tissues examined, whereas MPLA was not dephosphorylated. When mice received AP immediately after the LPS challenge, the survival rate was 100%, over 57% in the control group. We conclude that the enzymatic removal of phosphate groups from LPS by AP represents a crucial detoxification reaction, which may provide a new strategy to treat LPS-induced diseases like sepsis.
. In normal rats, 125IrhIL-10 rapidly disappears from the circulation, and the kidney is predominantly responsible for this. In BDL-3 rats, the liver largely contributes to this rapid plasma disappearance, probably due to an increase in IL-10 receptor expression. The extensive renal clearance of IL-10 in vivo may limit a clinical application of this cytokine for the treatment of chronic liver diseases. To optimize the therapeutic effects of IL-10 in hepatic diseases, alternative approaches that either decrease renal disposition or that further enhance hepatic delivery should be considered.
Inhibition of TGF-beta signaling by local drug delivery is a promising antifibrotic strategy, and demonstrated the important role of tubular activation in renal fibrosis.
ABSTRACT:In previous studies, we have demonstrated that the low molecular weight protein lysozyme can be used as a renal-selective drug carrier for delivery of the angiotensin-converting enzyme (ACE) inhibitor captopril. Typically, such macromolecular drug-targeting preparations are administered intravenously. In the present study, we investigated the fate of captopril-lysozyme following subcutaneous administration, a convenient route for long-term treatment. The absorption from the subcutaneous injection site and renal uptake of lysozyme were determined by gamma scintigraphy in rats. Bioavailability, renal accumulation, and stability of the captopril-lysozyme conjugate were evaluated by high performance liquid chromatography analysis and by ACE activity measurements.Lysozyme was absorbed gradually and completely from the subcutaneous injection site within 24 h and accumulated specifically in kidneys. After subcutaneous injection of the captopril-lysozyme conjugate, higher renal captopril levels and lower captoprillysozyme levels in urine indicated the improved renal accumulation in comparison with intravenous administration of the conjugate, as well as its stability at the injection site. After both treatments, captopril-lysozyme conjugate effectuated renal ACE inhibition, whereas plasma ACE was not inhibited. In conclusion, our results demonstrate that we can use the subcutaneous route to administer drug delivery preparations like the captopril-lysozyme conjugate.
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