BACKGROUND: Crescentic glomerulonephritis is a rapidly progressive form of glomerulonephritis, but treatment remains non-specific. The methylxanthine derivative pentoxifylline (PTX) is a clinically available phosphodiesterase inhibitor with anti-inflammatory and immunoregulatory activities. This study examined whether PTX has beneficial effects in a rat model of anti-glomerular basement membrane (GBM) crescentic glomerulonephritis. METHODS: Experimental crescentic glomerulonephritis was induced in Wistar rats by intravenous injection of rabbit anti-rat GBM serum and treated with either vehicle (phosphate-buffered saline) or PTX (0.1 g/kg/day) intravenously on a daily basis. Groups of six animals were euthanized at days 3, 7, 14 or 28 after induction of disease. Effects of PTX on renal function, histology and expression of cytokines, chemokines and adhesion molecules were determined. RESULTS: Compared with the vehicle-treated nephritic rats, PTX treatment beginning at the start of the nephritis significantly suppressed mRNA expression of tumour necrosis factor (TNF)-alpha, but not interleukin-1 beta, throughout the course of nephritis. Moreover, PTX decreased renal mRNAs for intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1), regulated on activation, normal T-cell expressed and secreted (RANTES) and osteopontin (OPN) at all time points examined. These effects were associated with a significant inhibition of macrophage and T-cell infiltration, a reduction of 24-h urinary protein excretion (50-75%, P<0.05), an improvement of histological damage including glomerular crescent formation (60-70%, P<0.01) and a decrease of cortical mRNAs for type I (alpha 1) collagen and fibronectin. The efficacy of PTX could also be seen, though to a lesser extent, in rats with established nephritis. CONCLUSIONS: PTX is an effective anti-inflammatory and immunomodulatory agent capable of suppressing rat crescentic glomerulonephritis. Inhibition of renal TNF-alpha, ICAM-1, RANTES, MCP-1 and OPN expression may be a mechanism whereby PTX suppresses progressive renal injury in rat crescentic glomerulonephritis.
BACKGROUND: Crescentic glomerulonephritis is a rapidly progressive form of glomerulonephritis, but treatment remains non-specific. The methylxanthine derivative pentoxifylline (PTX) is a clinically available phosphodiesterase inhibitor with anti-inflammatory and immunoregulatory activities. This study examined whether PTX has beneficial effects in a rat model of anti-glomerular basement membrane (GBM) crescentic glomerulonephritis. METHODS: Experimental crescentic glomerulonephritis was induced in Wistar rats by intravenous injection of rabbit anti-rat GBM serum and treated with either vehicle (phosphate-buffered saline) or PTX (0.1 g/kg/day) intravenously on a daily basis. Groups of six animals were euthanized at days 3, 7, 14 or 28 after induction of disease. Effects of PTX on renal function, histology and expression of cytokines, chemokines and adhesion molecules were determined. RESULTS: Compared with the vehicle-treated nephritic rats, PTX treatment beginning at the start of the nephritis significantly suppressed mRNA expression of tumour necrosis factor (TNF)-alpha, but not interleukin-1 beta, throughout the course of nephritis. Moreover, PTX decreased renal mRNAs for intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1), regulated on activation, normal T-cell expressed and secreted (RANTES) and osteopontin (OPN) at all time points examined. These effects were associated with a significant inhibition of macrophage and T-cell infiltration, a reduction of 24-h urinary protein excretion (50-75%, P<0.05), an improvement of histological damage including glomerular crescent formation (60-70%, P<0.01) and a decrease of cortical mRNAs for type I (alpha 1) collagen and fibronectin. The efficacy of PTX could also be seen, though to a lesser extent, in rats with established nephritis. CONCLUSIONS:PTX is an effective anti-inflammatory and immunomodulatory agent capable of suppressing rat crescentic glomerulonephritis. Inhibition of renal TNF-alpha, ICAM-1, RANTES, MCP-1 and OPN expression may be a mechanism whereby PTX suppresses progressive renal injury in rat crescentic glomerulonephritis.
Authors: Bruce M Hendry; Nina Stafford; Ahran D Arnold; Arvind Sangwaiya; Vijay Manglam; Stuart D Rosen; Jayantha Arnold Journal: Pharmacol Res Perspect Date: 2020-08