Effects of C‐reactive protein and pentosan polysulphate on human complement activation

Abstract

SUMMARYComplement (C) activation is believed to play an adverse role in several chronic degenerative disease processes, including atherosclerosis, myocardial infarction and Alzheimer's disease. We developed several in vitro quantitative assays to evaluate processes which activate C in human serum, and to assess candidates which might block that activation. Binding of C-reactive protein (CRP) to immobilized cell surfaces was used as a tissue-based method of activation, while immunoglobulin G in solution was used as a surrogate antibody method. Activation was assessed by deposition of C fragments on fixed cell surfaces, or by capture of C5b-9 from solution. We observed that several cell lines, including SH-SY5Y, U-937, THP-1 and ECV304, bound CRP and activated C following attachment of cells to a plastic surface by means of air drying. Treatment of human neuroblastoma SH-SY5Y cells with the reactive oxygen intermediates generated by xanthine (Xa) -xanthine oxidase (XaOx) prior to air drying or by hydrogen peroxide solutions after air drying, enhanced C activation, possibly through oxidation of the cell lipid membrane. Several C inhibitors were tested for their effectiveness in blocking these systems. Pentosan polysulphate (PPS), an orally active agent, blocked C activation in the same concentration range of 1-1000 mg /ml as heparin, dextran sulphate, compstatin and fucoidan. PPS may have practical application as a C inhibitor.

Disease-associated glycosylated molecular variants of human C-reactive protein activate complement-mediated hemolysis of erythrocytes in tuberculosis and Indian visceral leishmaniasis

“…The observed hemolysis in our studies confirmed that CRP-mediated complement-activation ends with consumption of terminal membrane attack complex (MAC). Though most of the reported CRP-mediated complement-activation is essentially limited to stage involving C1-C4 [73] some reports also suggested deposition of MAC by CRP [40,74]. Therefore, our results are consistent with these reports revealing CRP-complement activation by binding with erythrocyte-CRP.…”

Sodium Pentosan Polysulfate Reduced Renal Ischemia-Reperfusion-Induced Oxidative Stress and Inflammatory Responses in an Experimental Animal Model

“…The anti-inflammatory action of the pentosan polysulfate is not clearly understood. It is reported that PPS decreases lipopolysaccharide-mediated NF-κB activation, suppresses leukocyte elastase, and inhibits complement activity [16,17,18]. It has been demonstrated that PPS decreases tubulointerstitial inflammation and preserves renal function in 5/6 nephrectomized rats [19].…”

Inhibition of inflammation by pentosan polysulfate impedes the development and progression of severe diabetic nephropathy in aging C57B6 mice

“…It is reported that PPS decreases lipopolysaccharide-mediated NFkB activation, suppresses leukocyte elastase and inhibits complement activity. [15][16][17] As PPS has been found to substantially decrease tubulointerstitial inflammation and preserve renal function in 5/6 nephrectomized rats, 18 we asked if the antiinflammatory effect of PPS reduced DN in aging mice, which develop severe nephropathy, including typical tubulointerstitial inflammatory lesions. We also tested the effect of PPS on high glucose, AGEs and TNF-a-stimulated inflammation in renal cells in vitro.…”