Mechanisms of Vascular Damage in Gout and Oxalosis: Crystal Induced, Granulocyte Mediated, Endothelial Injury

Summary

Immune triggered granulocyte (PMN)-endothelial interactions have been implicated in the pathogenesis of vascular diseases. While hyperuricemia and gout are associated with an increased risk of atherogenesis, we studied the modulation by mono- sodiumurate (MSU) crystals of PMN-endothelial interactions in vitro. The relationship between calciumoxalate (COX) crystals - implicated in the vasculitis of primary oxalosis - and immunologically mediated endothelial injury was also explored.

Both MSU- and COX-crystals activate complement (C), as illustrated by the finding of strong PMN aggregating activity and large amounts of C^3a and C^5a-anaphylatoxin in MSU- and COX- crystal incubated sera.

MSU- and COX-crystal treated sera stimulate PMN to adhere to and induce significant ⁵¹Cr-release from endothelial cells in vitro. Platelets significantly increase crystal-triggered PMN endothelial cell adherence and ⁵¹Cr-release. This platelet augmenting effect depends on the release of platelet constituents (e. g. serotonin).

Microcrystalline material present in vessel walls, thus may cause C-activation and may trigger PMN and platelets to damage endothelium in vitro and in vivo. These findings may have relevance to the understanding of the accelerated atherogenesis of hyperuricemia and the fulminant vasculitis of oxalosis or ethylene glycol poisoning.

Keywords

Hyperuricemia - Gout - Oxalosis - Endothelium - Granulocytes - Immune damage - Complement

• References

• 1 Hasselbacher P. Crystal-protein interactions in crystal induced arthritis. Advances in Inflammation Research. Weissmann G. (Ed) Raven Press; New York: 1982. pp 25-44
• 2 Rae SE, Davidson EM, Smith MJ. Leukotriene B an inflammatory mediator in gout. Lancet 1982; 2: 1121-1122
• 3 Phelps P, McCarthy DJ. Crystal-induced inflammation in canine joints: Importance of Polymorphonuclear leukocytes. J Exp Med 1966; 124: 115-117
• 4 Yamada O, Moldow CF, Sacks T, Craddock PR, Boogaerts MA, Jacob HS. Deleterious effects of endotoxin on cultured endothelial cells. Inflammation 1981; 5: 115-119
• 5 Boogaerts MA, Yamada O, Jacob HS, Moldow CF. Enhancement of granulocyte-endothelial cell adherence and granulocyte induced cytotoxicity by platelet release products. Proc Natl Acad Sci USA 1982; 79: 7019-7023
• 6 Boogaerts MA, Jacob HS, Yamada O, Kramer P, Moldow CF. The neurohormones serotonin and enkephalin modulate endothelial cell damage in vitro: ramifications for stress-related atherosclerosis. Clin Res 1980; 38: 490
• 7 Fessel WJ, Siegelant AB. Correlations and consequences of asymptomatic hyperuricemia. Arch Int Med 1973; 132: 44-49
• 8 Boss GR, Seguiller JE. Hyperuricemia and gout. N Engl J Med 1979; 300: 1459-1465
• 9 Bunim JJ. McEwan. Tophus of mitral valva in gout. Arch Pathol 1960; 29: 700-704
• 10 Trant EF, Knight AA. Specific vascular changes in gout. JAMA 1954; 156: 591-602
• 11 Greenberg CS, Hammerschmidt DE, Craddock PR, Jacob HS. Atheroma cholesterol activates complement and aggregates granulocytes. Possible role in ischemic manifestations of atherosclerosis Trans Assoc Am Phys 1979; 92: 130-135
• 12 Case reports Massachussets General Hospital. N Engl J Med. 1979 300. 909-914
• 13 Friedman EA, Greenberg JB, Mervill JP. Consequences of ethylene glycol poisoning: report of four cases and review of the literature. Am J Med 1962; 891-896
• 14 Boyum A. Isolation of mononuclear cells and granulocytes from human blood. Scand J Clin Lab Invest 1968; 21: 77-89
• 15 Ginsberg MH, Kozin F, O’Malley M, Mc CarthyD. Release of platelet constituents by monosodium urate crystals. J Clin Invest 1977; 60: 999-1007
• 16 Hammerschmidt DE, Bowers TK, Lammi-Keefe CJ, Jacob HS, Craddock PR. Granulocyte aggregometry: a sensitive technique for the detection of C_5a and complement activation. Blood 1980; 55: 898-902
• 17 Goldstein IM, Roos D, Kaplan HB, Weisman G. Complement and immunoglobulin stimulate superoxyde production by human leukocytes independently of phagocytosis. J Clin Invest 1975; 56: 1155-1160
• 18 Nelson RD, Herron MJ, Schmidtke K, Simmons L. Chemiluminescence response of human leukocytes: influences of medium components on light production. Infect Immun 1977; 17: 513-516
• 19 Nelson RA, Quie PG, Simmons RL. Chemotaxis under agarose: a new and simple method for measuring chemotaxis and spontaneous migration of human polymorphonuclear leukocytes and monocytes. J Immunol 1975; 115: 1650-1656
• 20 Chatelet de LR, Wang D. McCall. Hexose monophosphate shunt activity and O₂-consumption during phagocytosis. Soc Exp Med Proc 1972; 140: 1434-1437
• 21 Jaffe EA, Nachman RL, Backer CG, Minick CR. Culture of human endothelial cells, derived from umbilical veins: identification by morphologic and immunologic criteria. J Clin Invest 1973; 52: 2745-2756
• 22 Fehr J, Jacob HS. In vitro granulocyte adherence and in vivo margination, two associated complement dependent functions. J Exp Med 1977; 146: 641-645
• 23 Hugh TE, Chenoweth DE. Biologically active peptides of complement: techniques and significance of C_3a and C_5a measurements. In Immunoassays: clinical laboratory techniques for the 1980. Nakamura RM, Dito WR, Tucker ES. (eds) Allan R Liss, Inc; New York: 1980. pp 443-460
• 24 Naff GB, Byars PH. Complement as a mediator of inflammation in acute gouty arthritis. J Lab Clin Med 1973; 81: 747-760
• 25 Gielas DC, Ginsberg MH, Cooper NR. Immunoglobulin C independent activation of the classical complement pathway by monosodium urate crystals. J Clin Invest 1979; 63: 759-764
• 26 Hammerschmidt DE, Boogaerts MA, Greenberg CS, Raij L, Moldow CF, Jacob HS. Crystalline urate or oxalate activate complement, provoking PMN to damage endothelial cells. Clin Res 1980; 28: 348 (Abstr.)
• 27 Skubitz KM, Craddock PR, Hammerschmidt DE, August TJ. Corticosteroids block binding of chemotactic peptide to its receptor on granulocytes and cause disaggregation of granulocyte aggregates in vitro. J Clin Invest 1981; 68: 13-20
• 28 Mustard JF, Murphy EA, Ogryzlo MA, Smythe HA. Blood coagulation and platelet economy in subjects with primary gout. Can Med Ass J 1963; 89: 1207-1212
• 29 Redl H, Hammerschmidt DE, Schlag G. Augmentation by platelets of granulocyte aggregation in response to chemotaxis: studies utilizing an improved cell preparation technique. Blood 1983; 61: 125-131