Macrophage depletion by albumin microencapsulated clodronate: attenuation of cytokine release in macrophage-dependent glomerulonephritis.
A macrophage plays an important role in mediating the inflammatory response. Cytokines released by activated macrophages contribute to inflammation in glomerulonephritis (GN). Clodronate, a biphosphonate, causes macrophage depletion when administered in an encapsulated form in liposomes. We used albumin as the polymer matrix to microencapsulate clodronate to the microspheres (MS) in the 1-micron size range. The purpose of this study was to (a) determine macrophage depletion by clodronate MS, (b) determine the effect of clodronate MS on endotoxin-induced cytokine release in vitro, and (c) assess the effect of clodronate MS on macrophage infiltration in experimental antiglomerular basement membrane nephritis. Macrophage depletion by clodronate MS was assessed by staining for the EDI marker. The results indicate greater than 95% depletion of macrophages from the spleen, liver, kidney, and blood. In the whole blood model, clodronate MS attenuated endotoxin-induced tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) release, and the attenuation by the microencapsulated form of clodronate was also more effective than the free (solution) form of clodronate. Macrophage infiltration into the glomerulus in experimental GN was also blocked very effectively by pretreatment with clodronate MS. In conclusion, macrophage depletion by clodronate MS may be beneficial in reducing cytokine release and renal damage in GN.
D'Souza
M J
MJ
Department of Pharmaceutical Sciences, Southern College of Pharmacy, Mercer University, Atlanta, Georgia 30341, USA.
Oettinger
C W
CW
Shah
A
A
Tipping
P G
PG
Huang
X R
XR
Milton
G V
GV
D000418:Albumins / Q000008:administration & dosage*; D000818:Animals; D004002:Clodronic Acid / Q000008:administration & dosage*; D005921:Glomerulonephritis / Q000188:drug therapy*; D007375:Interleukin-1 / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects*; D008863:Microspheres; D051381:Rats; D011916:Rats, Inbred F344; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000418:Albumins; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D004002:Clodronic Acid